{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T19:46:35Z","timestamp":1792525595314,"version":"4.5.0"},"reference-count":188,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,11,3]],"date-time":"2021-11-03T00:00:00Z","timestamp":1635897600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004281","name":"National Science Center","doi-asserted-by":"publisher","award":["2016\/21\/B\/NZ5\/01901"],"award-info":[{"award-number":["2016\/21\/B\/NZ5\/01901"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Interleukin (IL)-4 and IL-13 belong to the T helper 2 (Th2) cytokine family, along with IL-3, IL-5, and IL-9. These cytokines are key mediators of allergic inflammation. They have important immunomodulatory activities and exert influence on a wide variety of immune cells, such as B cells, eosinophils, basophils, monocytes, fibroblasts, endothelial cells, airway epithelial cells, smooth muscle cells, and keratinocytes. Recent studies have implicated IL-4 and IL-13 in the development of various autoimmune diseases. Additionally, these cytokines have emerged as potential players in pathogenesis of inflammatory arthritis. Recent findings suggest that the IL-4 and IL-13 might play a significant role in the downregulation of inflammatory processes underlying RA pathology, and beneficially modulate the course of the disease. This review summarizes the biological features of the IL-4 and IL-13 and provides current knowledge regarding the role of these cytokines in inflammatory arthritis.<\/jats:p>","DOI":"10.3390\/cells10113000","type":"journal-article","created":{"date-parts":[[2021,11,3]],"date-time":"2021-11-03T17:59:38Z","timestamp":1635962378000},"page":"3000","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":297,"title":["Significance of Interleukin (IL)-4 and IL-13 in Inflammatory Arthritis"],"prefix":"10.3390","volume":"10","author":[{"given":"Milena","family":"Iwaszko","sequence":"first","affiliation":[{"name":"Laboratory of Clinical Immunogenetics and Pharmacogenetics, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-144 Wroc\u0142aw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylwia","family":"Bia\u0142y","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Immunogenetics and Pharmacogenetics, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-144 Wroc\u0142aw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9744-0376","authenticated-orcid":false,"given":"Katarzyna","family":"Bogunia-Kubik","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Immunogenetics and Pharmacogenetics, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-144 Wroc\u0142aw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1101\/gr.7.5.495","article-title":"Computational and biological analysis of 680 kb of DNA sequence from the human 5q31 cytokine gene cluster region","volume":"7","author":"Frazer","year":"1997","journal-title":"Genome Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"679","DOI":"10.4049\/jimmunol.142.2.679","article-title":"A family of small inducible proteins secreted by leukocytes are members of a new superfamily that includes leukocyte and fibroblast-derived inflammatory agents, growth factors, and indicators of various activation processes","volume":"142","author":"Brown","year":"1989","journal-title":"J. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"5436","DOI":"10.4049\/jimmunol.150.12.5436","article-title":"Structural comparison and chromosomal localization of the human and mouse IL-13 genes","volume":"150","author":"McKenzie","year":"1993","journal-title":"J. Immunol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1038\/362248a0","article-title":"Interleukin-13 is a new human lymphokine regulating inflammatory and immune responses","volume":"362","author":"Minty","year":"1993","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1006\/jmbi.2001.4765","article-title":"Solution structure of interleukin-13 and insights into receptor engagement","volume":"310","author":"Eisenmesser","year":"2001","journal-title":"J. Mol. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1006\/jmbi.2001.4764","article-title":"Solution structure of human IL-13 and implication for receptorbinding","volume":"310","author":"Moy","year":"2001","journal-title":"J. Mol. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/S0167-4889(02)00318-X","article-title":"Structure, binding, and antagonists in the IL-4\/IL-13 receptorsystem","volume":"1592","author":"Mueller","year":"2002","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1556\/030.62.2015.4.2","article-title":"Interleukin-13 as an important cytokine: A review on its roles in some human diseases","volume":"62","author":"Seyfizadeh","year":"2015","journal-title":"Acta Microbiol. Immunol. Hung."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1084\/jem.155.3.914","article-title":"Identification of a T-cell derived B cell growth factor distinct from interleukin-2","volume":"155","author":"Howard","year":"1982","journal-title":"J. Exp. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1038\/319640a0","article-title":"Cloning of cDNA encoding the murine IgG1 induction factor by a novel strategy using SP6 promoter","volume":"319","author":"Noma","year":"1986","journal-title":"Nature"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"5894","DOI":"10.1073\/pnas.83.16.5894","article-title":"Isolation and characterization of a human interleukin cDNA clone, homologous to mouse B-cell stimulatory factor 1, that expresses B-cell- and T-cell-stimulating activities","volume":"83","author":"Yokota","year":"1986","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3109\/08830189809084486","article-title":"Interleukin-4 and interleukin-13: Their similarities and discrepancies","volume":"17","author":"Chomarat","year":"1998","journal-title":"Int. Rev. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"20371","DOI":"10.1016\/S0021-9258(19)88711-2","article-title":"Crystal structure of recombinant human interleukin-4","volume":"267","author":"Walter","year":"1992","journal-title":"J. Biol. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2322","DOI":"10.1002\/eji.201142227","article-title":"IL-13-producing Th1 and Th17 cells characterize adaptive responses to both self and foreign antigens","volume":"42","author":"Gallo","year":"2012","journal-title":"Eur. J. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1038\/ni.2182","article-title":"Divergent expression patterns of IL-4 and IL-13 define unique functions in allergic immunity","volume":"13","author":"Liang","year":"2011","journal-title":"Nat. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1146\/annurev.iy.07.040189.001045","article-title":"TH1 and TH2 Cells: Different Patterns of Lymphokine Secretion Lead to Different Functional Properties","volume":"7","author":"Mosmann","year":"1989","journal-title":"Annu. Rev. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.cyto.2015.01.038","article-title":"History of interleukin-4","volume":"75","author":"Paul","year":"2015","journal-title":"Cytokine"},{"key":"ref_18","first-page":"55","article-title":"Untangling the complex web of IL-4- and IL-13-mediated signaling pathways","volume":"1","author":"Finkelman","year":"2008","journal-title":"Sci. Signal."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1111\/j.0105-2896.2004.00192.x","article-title":"Interleukin-4- and interleukin-13-mediated host protection against intestinal nematode parasites","volume":"201","author":"Finkelman","year":"2004","journal-title":"Immunol. Rev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.cyto.2015.05.014","article-title":"IL-4 and IL-13 signaling in allergic airway disease","volume":"75","author":"Gour","year":"2015","journal-title":"Cytokine"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1387","DOI":"10.3389\/fphar.2019.01387","article-title":"The intriguing role of interleukin 13 in the pathophysiology of asthma","volume":"10","author":"Marone","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3735","DOI":"10.1073\/pnas.90.8.3735","article-title":"Interleukin 13, a T-cell-derived cytokine that regulates human monocyte and B-cell function","volume":"90","author":"McKenzie","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2258","DOI":"10.1126\/science.282.5397.2258","article-title":"Interleukin-13: Central mediator of allergic asthma","volume":"282","author":"Luyimbazi","year":"1998","journal-title":"Science"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1084\/jem.173.3.747","article-title":"Human B cell clones can be induced to proliferate and to switch to IgE and IgG4 synthesis by interleukin 4 and a signal provided by activated CD4+ T cell clones","volume":"173","author":"Gascan","year":"1991","journal-title":"J. Exp. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"6880","DOI":"10.1073\/pnas.85.18.6880","article-title":"IgE production by normal human lymphocytes is induced by interleukin 4 and suppressed by interferons gamma and\u00b7and prostaglandin E2","volume":"85","author":"Rousset","year":"1988","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3730","DOI":"10.1073\/pnas.90.8.3730","article-title":"Interleukin 13 induces interleukin 4-independent IgG4 and IgE synthesis and CD23 expression by human B cells","volume":"90","author":"Punnonen","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1084\/jem.179.1.135","article-title":"Interleukin 13 is a B cell stimulating factor","volume":"179","author":"Defrance","year":"1994","journal-title":"J. Exp. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1094","DOI":"10.4049\/jimmunol.152.3.1094","article-title":"IL-13 induces proliferation, Ig isotype switching, and Ig synthesis by immature human fetal B cells","volume":"152","author":"Punnonen","year":"1994","journal-title":"J. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1859","DOI":"10.1182\/blood.V77.9.1859.1859","article-title":"Interleukin-4: A prototypic immunoregulatory lymphokine","volume":"77","author":"Paul","year":"1991","journal-title":"Blood"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1016\/S0091-6749(95)70199-0","article-title":"Functional significance of IL-4 receptor on B cells in IL-4-induced human IgE production","volume":"96","author":"Yanagihara","year":"1995","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4286","DOI":"10.1182\/blood.V87.10.4286.bloodjournal87104286","article-title":"Interleukin-4 (IL-4) and IL-13 bind to a shared heterodimeric complex on endothelial cells mediating vascular cell adhesion molecule-1 induction in the absence of the common gamma chain","volume":"87","author":"Schnyder","year":"1996","journal-title":"Blood"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1016\/S0960-9822(98)70256-8","article-title":"Differences between IL-4R\u03b1-deficient and IL-4-deficient mice reveal a role for IL-13 in the regulation of Th2 responses","volume":"8","author":"Barner","year":"1998","journal-title":"Curr. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1159\/000024182","article-title":"Early interleukin-4: Its role in the switch towards a Th2 response and IgE-mediated allergy","volume":"119","author":"Haas","year":"1999","journal-title":"Int. Arch. Allergy Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1038\/43213","article-title":"A new protein containing an SH2 domain that inhibits JAK kinases","volume":"387","author":"Endo","year":"1997","journal-title":"Nature"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1038\/43206","article-title":"A family of cytokine- inducible inhibitors of signalling","volume":"387","author":"Starr","year":"1997","journal-title":"Nature"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1067\/mai.2003.1333","article-title":"IL-13 receptors and signaling pathways: An evolving web","volume":"111","author":"Hershey","year":"2003","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1002\/1521-1878(200007)22:7<646::AID-BIES7>3.0.CO;2-9","article-title":"The role of interleukin-13 in infectious diseases and allergy","volume":"22","author":"Brombacher","year":"2000","journal-title":"Bioessays"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/S0091-6749(98)70080-6","article-title":"The role of IL-13 and its receptor in allergy and inflammatory responses","volume":"102","year":"1998","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1002\/1529-0131(200101)44:1<3::AID-ANR2>3.0.CO;2-U","article-title":"Synergistic activity of interleukin-4 and interleukin-10 in suppression of inflammation and joint destruction in rheumatoid arthritis","volume":"44","author":"Lafeber","year":"2001","journal-title":"Arthritis Rheum."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1111\/imm.12910","article-title":"Implications of macrophage polarization in autoimmunity","volume":"154","author":"Funes","year":"2018","journal-title":"Immunology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1615\/CritRevImmunol.2013007096","article-title":"Regulation of Th17 maturation by interleukin 4","volume":"33","author":"Cooney","year":"2013","journal-title":"Crit. Rev. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"5317","DOI":"10.4049\/jimmunol.0803868","article-title":"A functional IL-13 receptor is expressed on polarized murine CD4+ Th17 cells and IL-13 signaling attenuates Th17 cytokine production","volume":"182","author":"Newcomb","year":"2009","journal-title":"J. Immunol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.4049\/jimmunol.149.4.1283","article-title":"IL-4 reciprocally regulates IL-1 and IL-1 receptor antagonist expression in human monocytes","volume":"149","author":"Fenton","year":"1992","journal-title":"J. Immunol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.bbi.2012.11.006","article-title":"IL-1 receptor 2 (IL-1R2) and its role in immune regulation","volume":"32","author":"Peters","year":"2013","journal-title":"Brain Behav. Immun."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2236","DOI":"10.4049\/jimmunol.1700372","article-title":"IL-4\/IL-13 Heteroreceptor Influences Th17 Cell Conversion and Sensitivity to Regulatory T Cell Suppression to Restrain Experimental Allergic Encephalomyelitis","volume":"199","author":"Barik","year":"2017","journal-title":"J. Immunol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1080\/1744666X.2017.1279054","article-title":"The role of IL-4 in psoriasis","volume":"13","author":"Hahn","year":"2017","journal-title":"Expert Rev. Clin. Immunol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1038\/nm0901-1057","article-title":"Activation of natural killer T cells by \u03b1-galactosylceramide treatment prevents the onset and recurrence of autoimmune type 1 diabetes","volume":"7","author":"Sharif","year":"2001","journal-title":"Nat. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/s41584-018-0109-2","article-title":"Anti-inflammatory and immune-regulatory cytokines in rheumatoid arthritis","volume":"15","author":"Chen","year":"2019","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"29265","DOI":"10.1074\/jbc.271.46.29265","article-title":"cDNA cloning and characterization of the human interleukin 13 receptor alpha chain","volume":"271","author":"Aman","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1073\/pnas.93.1.497","article-title":"Cloning and characterization of a binding subunit of the interleukin 13 receptor that is also a component of the interleukin 4 receptor","volume":"93","author":"Hilton","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"13869","DOI":"10.1074\/jbc.270.23.13869","article-title":"The primary binding subunit of the human interleukin-4 receptor is also a component of the interleukin-13 receptor","volume":"270","author":"Zurawski","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1146\/annurev.immunol.17.1.701","article-title":"The IL-4 receptor: Signaling mechanisms and biologic functions","volume":"17","author":"Nelms","year":"1999","journal-title":"Annu. Rev. Immunol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1007\/s12026-011-8205-2","article-title":"Transcriptional regulation by STAT6","volume":"50","author":"Goenka","year":"2011","journal-title":"Immunol. Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"888","DOI":"10.3389\/fimmu.2018.00888","article-title":"Tuning the cytokine responses: An update on interleukin (IL)-4 and IL-13 receptor complexes","volume":"9","author":"Junttila","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1527","DOI":"10.1126\/science.1085458","article-title":"Interleukin-4 and interleukin-13 signaling connections maps","volume":"300","author":"Hanson","year":"2003","journal-title":"Science"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"4286","DOI":"10.1002\/(SICI)1521-4141(199812)28:12<4286::AID-IMMU4286>3.0.CO;2-H","article-title":"The distribution of IL-13 receptor alpha1 expression on B cells, T cells and monocytes and its regulation by IL-13 and IL-4","volume":"28","author":"Graber","year":"1998","journal-title":"Eur. J. Immunol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1038\/nri.2017.118","article-title":"TH2 cell development and function","volume":"18","author":"Walker","year":"2018","journal-title":"Nat. Rev. Immunol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.cyto.2015.05.008","article-title":"The Differential Expression of IL-4 and IL-13 and Its Impact on Type-2 Immunity","volume":"75","author":"Bao","year":"2015","journal-title":"Cytokine"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1111\/1440-1681.12946","article-title":"The role of interleukin-4 in rheumatic diseases","volume":"45","author":"Dong","year":"2018","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.cyto.2015.05.010","article-title":"T helper 2 (Th2) cell differentiation, type 2 innate lymphoid cell (ILC2) development and regulation of interleukin-4 (IL-4) and IL-13 production","volume":"75","author":"Zhu","year":"2015","journal-title":"Cytokine"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2777","DOI":"10.1038\/jid.2009.169","article-title":"Association between IL13 polymorphisms and psoriatic arthritis is modified by smoking","volume":"129","author":"Duffin","year":"2009","journal-title":"J. Invest. Dermatol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"R80","DOI":"10.1186\/ar2454","article-title":"Lack of association or interactions between the IL-4, IL-4R\u03b1 and IL-13 genes, and rheumatoid arthritis","volume":"10","author":"Marinou","year":"2008","journal-title":"Arthritis Res. Ther."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1111\/iji.12065","article-title":"Relation of IL-6, IL-13 and IL-15 gene polymorphisms to the rheumatoid factors, anti-CCP and other measures of rheumatoid arthritis activity","volume":"41","author":"Nemec","year":"2014","journal-title":"Int. J. Immunogenet."},{"key":"ref_64","first-page":"15","article-title":"Correlation between IL-3 and IL-13 gene polymorphisms in Chinese patients and rheumatoid arthritis","volume":"23","author":"Wang","year":"2016","journal-title":"Genet. Mol. Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1594","DOI":"10.1136\/ard.2010.147421","article-title":"IL13 gene polymorphism is a marker for psoriatic arthritis among psoriasis patients","volume":"70","author":"Eder","year":"2011","journal-title":"Ann. Rheum. Dis."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1136\/ard.2010.143123","article-title":"Evidence to support IL-13 as a risk locus for psoriatic arthritis but not psoriasis vulgaris","volume":"70","author":"Bowes","year":"2011","journal-title":"Ann. Rheum. Dis."},{"key":"ref_67","first-page":"265435","article-title":"The effects of gene polymorphisms in interleukin-4 and interleukin-6 on the susceptibility of rheumatoid arthritis in a Chinese population","volume":"2014","author":"Li","year":"2014","journal-title":"Biomed. Res. Int."},{"key":"ref_68","first-page":"36","article-title":"Polymorphisms in the IL4 and IL4RA genes in Colombian patients with rheumatoid arthritis","volume":"34","author":"Moreno","year":"2007","journal-title":"J. Rheumatol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1007\/s00296-004-0539-9","article-title":"The -590 IL-4 promoter polymorphism in patients with rheumatoid arthritis","volume":"26","author":"Pawlik","year":"2005","journal-title":"Rheumatol. Int."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1016\/j.cyto.2013.01.001","article-title":"Influence of interleukin-4 gene polymorphisms and interleukin-4 serum level on susceptibility and severity of rheumatoid arthritis in Egyptian population","volume":"61","author":"Hussein","year":"2013","journal-title":"Cytokine"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1002\/1529-0131(199906)42:6<1093::AID-ANR5>3.0.CO;2-P","article-title":"Interleukin-1beta, interleukin-1 receptor antagonist, interleukin-4, and interleukin-10 gene polymorphisms: Relationship to occurrence and severity of rheumatoid arthritis","volume":"42","author":"Cantagrel","year":"1999","journal-title":"Arthritis Rheum."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1007\/s00251-007-0265-z","article-title":"IL4 in the 5q31 context: Association studies of type 1 diabetes and rheumatoid arthritis in the Spanish population","volume":"60","author":"Nunez","year":"2008","journal-title":"Immunogenetics"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1097\/FPC.0000000000000155","article-title":"Genetic variants within immune-modulating genes influence the risk of developing rheumatoid arthritis and anti-TNF drug response: A two-stage case-control study","volume":"25","author":"Canet","year":"2015","journal-title":"Pharmacogenet. Genom."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1016\/j.sjbs.2016.01.013","article-title":"Promoter polymorphism (-590, T\/C) of interleukin 4 (IL4) gene is associated with rheumatoid arthritis: An updated meta-analysis","volume":"24","author":"Park","year":"2017","journal-title":"Saudi J. Biol. Sci."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"3051","DOI":"10.1002\/art.38141","article-title":"Association of genetic variants in the IL4 and IL4R genes with the severity of joint damage in rheumatoid arthritis: A study in seven cohorts","volume":"65","author":"Krabben","year":"2013","journal-title":"Arthritis Rheum."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1002\/art.10394","article-title":"Association of interleukin-4 and interleukin-1B gene variants with Larsen score progression in rheumatoid arthritis","volume":"47","author":"Genevay","year":"2002","journal-title":"Arthritis Rheum."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1126","DOI":"10.1093\/rheumatology\/39.10.1126","article-title":"IL-4 VNTR gene polymorphism in chronic polyarthritis. The rare allele is associated with protection against destruction","volume":"39","author":"Buchs","year":"2000","journal-title":"Rheumatology"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1491","DOI":"10.1002\/art.21832","article-title":"Association of the IL4R single-nucleotide polymorphism I50V with rapidly erosive rheumatoid arthritis","volume":"54","author":"Prots","year":"2006","journal-title":"Arthritis Rheum."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1089\/gtmb.2013.0186","article-title":"Associations of interleukin-4 receptor gene polymorphisms (Q551R, I50V) with rheumatoid arthritis: Evidence from a meta-analysis","volume":"17","author":"Peng","year":"2013","journal-title":"Genet. Test. Mol. Biomark."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"R15","DOI":"10.1186\/ar3239","article-title":"A polymorphism in the interleukin-4 receptor affects the ability of interleukin-4 to regulate Th17 cells: A possible immunoregulatory mechanism for genetic control of the severity of rheumatoid arthritis","volume":"13","author":"Wallis","year":"2011","journal-title":"Arthritis Res. Ther."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"4023","DOI":"10.1002\/art.22278","article-title":"Lack of genetic association of the interleukin-4 receptor single-nucleotide polymorphisms I50V and Q551R with erosive disease in psoriatic arthritis","volume":"54","author":"Lascorz","year":"2006","journal-title":"Arthritis Rheum."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1693","DOI":"10.1002\/art.1780391012","article-title":"The presence of interleukin-v13 in rheumatoid synovium and its antiinflammatory effects on synovial fluid macrophages from patients with rheumatoid arthritis","volume":"39","author":"Luukkainen","year":"1996","journal-title":"Arthritis Rheum."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1136\/ard.61.2.174","article-title":"Interleukin 13 in synovial fluid and serum of patients with psoriatic arthritis","volume":"61","author":"Spadaro","year":"2002","journal-title":"Ann. Rheum. Dis."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1093\/rheumatology\/kel306","article-title":"Circulating cytokines in Norwegian patients with psoriatic arthritis determined by a multiplex cytokine array system","volume":"46","author":"Szodoray","year":"2007","journal-title":"Rheumatology"},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Silosi, I., Boldeanu, M.V., Cojocaru, M., Biciusca, V., Padureanu, V., Bogdan, M., Badea, R.G., Avramescu, C., Petrescu, I.O., and Petrescu, F. (2016). The relationship of cytokines IL-13 and IL-17 with autoantibodies profile in early rheumatoid arthritis. J. Immunol. Res., 3109135.","DOI":"10.1155\/2016\/3109135"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"R52","DOI":"10.1186\/ar3295","article-title":"Soluble interleukin-18 receptor complex is a novel biomarker in rheumatoid arthritis","volume":"13","author":"Takei","year":"2011","journal-title":"Arthritis Res. Ther."},{"key":"ref_87","first-page":"454","article-title":"High levels of interleukin 13 in rheumatoid arthritis sera are modulated by tumor necrosis factor antagonist therapy: Association with dendritic cell growth activity","volume":"29","author":"Tokayer","year":"2002","journal-title":"J. Rheumatol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"R784","DOI":"10.1186\/ar1733","article-title":"Early rheumatoid arthritis is characterized by a distinct and transient synovial fluid cytokine profile of T cell and stromal cell origin","volume":"7","author":"Raza","year":"2005","journal-title":"Arthritis Res. Ther."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1727","DOI":"10.1007\/s00296-017-3774-6","article-title":"Patterns of circulatory and peripheral blood mononuclear cytokines in rheumatoid arthritis","volume":"37","author":"Azizieh","year":"2017","journal-title":"Rheumatol. Int."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1006\/clin.1997.4441","article-title":"Low-level production of interleukin-13 in synovial fluid and tissue from patients with arthritis","volume":"85","author":"Woods","year":"1997","journal-title":"Clin. Immunol. Immunopathol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"80","DOI":"10.3899\/jrheum.130539","article-title":"Serum cytokine profile of unaffected first-degree relatives of patients with rheumatoid arthritis","volume":"41","author":"Barra","year":"2014","journal-title":"J. Rheumatol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1002\/1529-0131(199801)41:1<48::AID-ART7>3.0.CO;2-K","article-title":"Antiinflammatory and Immunoregulatory Action of Methotrexate in the Treatment of Rheumatoid Arthritis: Evidence of Increased Interleukin-4 and interleukin-10 Gene Expression Demonstrated In Vitro by Competitive Reverse Transcriptase-Polymerase Chain Reaction","volume":"41","author":"Constantin","year":"1998","journal-title":"Arthritis Rheum."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1180","DOI":"10.1002\/art.1780330819","article-title":"Low levels of interleukin-4 and high levels of transforming growth factor p in rheumatoid synovitis","volume":"33","author":"Miossec","year":"1990","journal-title":"Arthritis Rheum."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"8562","DOI":"10.1073\/pnas.91.18.8562","article-title":"Divergent T-cell cytokine patterns in inflammatory arthritis","volume":"91","author":"Simon","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1007\/s10875-005-4092-4","article-title":"mRNA quantification of T-bet, GATA-3, IFN-gamma, and IL-4 shows a defective Th1 immune response in the peripheral blood from rheumatoid arthritis patients: Link with disease activity","volume":"25","author":"Kawashima","year":"2005","journal-title":"J. Clin. Immunol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1023\/A:1023278606036","article-title":"Increased production of a Th2 cytokine profile by activated whole blood cells from rheumatoid arthritis patients","volume":"18","author":"Haddad","year":"1998","journal-title":"J. Clin. Immunol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1136\/ard.56.11.656","article-title":"Decrease in peripheral type 1over type 2 T cell cytokine production in patients with rheumatoid arthritis correlates with an increase in severity of disease","volume":"56","author":"Verhoef","year":"1997","journal-title":"Ann. Rheum. Dis."},{"key":"ref_98","first-page":"112","article-title":"Rapid immunoprofiling of cytokines, chemokines and growth factors in patients with active rheumatoid arthritis using Luminex Multiple Analyte Profiling technology for precision medicine","volume":"37","author":"Bahlas","year":"2019","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_99","first-page":"155","article-title":"Different cytokine profiles in the synovial fluid of patients with osteoarthritis, rheumatoid arthritis and seronegative spondylarthropathies","volume":"14","author":"Schlaak","year":"1996","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1002\/art.27186","article-title":"Up-regulation of cytokines and chemokines predates the onset of rheumatoid arthritis","volume":"62","author":"Kokkonen","year":"2010","journal-title":"Arthritis Rheum."},{"key":"ref_101","first-page":"S159","article-title":"Correlation of immune parameters with clinical response to methotrexate in patients with rheumatoid a prospective study [abstract]","volume":"3","author":"Kremer","year":"1991","journal-title":"Arthritis Rheum."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1046\/j.1365-2567.1999.00712.x","article-title":"Synovial fluid T cells from patients with rheumatoid arthritis are refractory to the Th2 differentiation inducing effects of IL-4","volume":"96","author":"Luukkainen","year":"1999","journal-title":"Immunology"},{"key":"ref_103","first-page":"1928","article-title":"CCR3, CCR5, interleukin 4, and interferon-\u03b3 expression on synovial and peripheral T cells and monocytes in patients with rheumatoid arthritis","volume":"30","author":"Nissinen","year":"2003","journal-title":"J. Rheumatol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"111","DOI":"10.3389\/fimmu.2020.00111","article-title":"Macrophage: A potential target on cartilage regeneration","volume":"11","author":"Fernandes","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1007\/s12016-015-8519-2","article-title":"Macrophage Polarization and Bone Formation: A review","volume":"51","author":"Horwood","year":"2016","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/S1471-4914(01)01963-3","article-title":"A crucial role for CD44 in inflammation","volume":"7","author":"Cuff","year":"2001","journal-title":"Trends Mol. Med."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/j.imbio.2017.11.001","article-title":"Macrophages: Their role, activation and polarization in pulmonary diseases","volume":"223","author":"Arora","year":"2018","journal-title":"Immunobiology"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.critrevonc.2016.08.002","article-title":"The role of IL-29 in immunity and cancer","volume":"106","author":"Kelm","year":"2016","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"17842","DOI":"10.1038\/s41598-021-96262-2","article-title":"Monocyte-derived and M1 macrophages from ankylosing spondylitis patients released higher TNF-\u03b1 and expressed more IL1B in response to BzATP than macrophages from healthy subjects","volume":"11","author":"Akhtari","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1002\/path.4466","article-title":"Macrophages from the synovium of active rheumatoid arthritis exhibit an activin A-dependent pro-inflammatory profile","volume":"235","author":"Izquierdo","year":"2015","journal-title":"J. Pathol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1046\/j.1365-2249.1999.00817.x","article-title":"Monocyte activation in rheumatoid arthritis (RA): Increased integrin, Fc gamma and complement receptor expression and the effect of glucocorticoids","volume":"115","author":"Torsteinsdottir","year":"1999","journal-title":"Clin. Exp. Immunol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/S1471-4906(02)02302-5","article-title":"Macrophage Polarization: Tumor-Associated Macrophages as a Paradigm for Polarized M2 Mononuclear Phagocytes","volume":"23","author":"Mantovani","year":"2002","journal-title":"Trends Immunol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"2213","DOI":"10.1159\/000374026","article-title":"IL-4 Modulates Macrophage Polarization in Ankylosing Spondylitis","volume":"35","author":"Lin","year":"2015","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"4344","DOI":"10.4049\/jimmunol.151.8.4344","article-title":"Suppression of monocyte function and differential regulation of IL-1 and IL-1ra by IL-4 contribute to resolution of experimental arthritis","volume":"15","author":"Allen","year":"1993","journal-title":"J. Immunol."},{"key":"ref_115","first-page":"261","article-title":"Macrophages in osteoarthritis: Pathophysiology and therapeutics","volume":"12","author":"Chen","year":"2020","journal-title":"Am. J. Transl. Res."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1038\/ni.1937","article-title":"Macrophage Plasticity and Interaction with Lymphocyte Subsets: Cancer as a Paradigm","volume":"11","author":"Biswas","year":"2010","journal-title":"Nat. Immunol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1038\/nri978","article-title":"Alternative Activation of Macrophages","volume":"3","author":"Gordon","year":"2003","journal-title":"Nat. Rev. Immunol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1146\/annurev-immunol-032712-095906","article-title":"Interleukin-4- and interleukin-13-mediated alternatively activated macrophages: Roles in homeostasis and disease","volume":"31","author":"Locksley","year":"2013","journal-title":"Annu. Rev. Immunol."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1038\/nri3831","article-title":"Type 2 cytokines: Mechanisms and therapeutic strategies","volume":"15","author":"Wynn","year":"2015","journal-title":"Nat. Rev. Immunol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"3","DOI":"10.3389\/fimmu.2019.00003","article-title":"Polarization of Rheumatoid Macrophages by TNF Targeting through an IL-10\/STAT3 Mechanism","volume":"10","author":"Degboe","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"1958","DOI":"10.3389\/fimmu.2017.01958","article-title":"M1 and M2 Monocytes in Rheumatoid Arthritis: A Contribution of Imbalance of M1\/M2 Monocytes to Osteoclastogenesis","volume":"8","author":"Fukui","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1111\/j.1365-2249.1995.tb05554.x","article-title":"Regulatory effects of IL-13 on synovial fluid macrophages and blood monocytes from patients with inflammatory arthritis","volume":"99","author":"Hart","year":"1995","journal-title":"Clin. Exp. Immunol."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1007\/s002960000074","article-title":"Differential in vitro effects of IL-4, IL-10, and IL-13 on proinflammatory cytokine production and fibroblast proliferation in rheumatoid synovium","volume":"20","author":"Morita","year":"2001","journal-title":"Rheumatol. Int."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1053\/joca.1997.0091","article-title":"Effect of IL-13 on cytokines, cytokine receptors and inhibitors on human osteoarthritis synovium and synovial fibroblasts","volume":"6","author":"Jovanovic","year":"1998","journal-title":"Osteoarthr. Cartil."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"1737","DOI":"10.1136\/ard.2004.034405","article-title":"Dendritic cells from patients with rheumatoid arthritis lack the interleukin 13 mediated increase of Fc gamma RII expression, which has clear functional consequences","volume":"64","author":"Radstake","year":"2005","journal-title":"Ann. Rheum. Dis."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"2775","DOI":"10.4049\/jimmunol.166.4.2775","article-title":"Il-4 and IL-13, but not IL-10, protect human synoviocytes from apoptosis","volume":"166","author":"Relic","year":"2001","journal-title":"J. Immunol."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1002\/jcb.10531","article-title":"IL-13 regulates vascular cell adhesion molecule-1 expression in human osteoblasts","volume":"89","author":"Rifas","year":"2003","journal-title":"J. Cell Biochem."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"6015","DOI":"10.4049\/jimmunol.167.10.6015","article-title":"Enhancing effect of IL-1, IL-17, and TNF-alpha on macrophage inflammatory protein-3 alpha production in rheumatoid arthritis: Regulation by soluble receptors and Th2 cytokines","volume":"167","author":"Chabaud","year":"2001","journal-title":"J. Immunol."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"874","DOI":"10.1002\/art.1780350805","article-title":"Inhibition of the production of proinflammatory cytokines and immunoglobulins by interleukin-4 in an ex vivo model of rheumatoid synovitis","volume":"35","author":"Miossec","year":"1992","journal-title":"Arthritis Rheum."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"3222","DOI":"10.1002\/eji.1830241247","article-title":"Interleukin-4 but not interleukin-10 inhibits the production of leukemia inhibitory factor by rheumatoid synovium and synoviocytes","volume":"24","author":"Dechanet","year":"1994","journal-title":"Eur. J. Immunol."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"2755","DOI":"10.4049\/jimmunol.165.5.2755","article-title":"Reduction of inflammatory cytokines and prostaglandin E2 by IL-13 gene therapy in rheumatoid arthritis synovium","volume":"165","author":"Woods","year":"2000","journal-title":"J. Immunol."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"3103","DOI":"10.1073\/pnas.1914186117","article-title":"IL-4 controls activated neutrophil Fc\u03b3R2b expression and migration into inflamed joints","volume":"117","author":"Panda","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1093\/rheumatology\/39.7.728","article-title":"Interleukin-4 inhibits interleukin-11 production by rheumatoid synovial cells","volume":"39","author":"Taki","year":"2000","journal-title":"Rheumatology"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"1398","DOI":"10.1002\/1529-0131(199808)41:8<1398::AID-ART8>3.0.CO;2-B","article-title":"Interleukin-4 suppression of interleukin-1\u2013induced transcription of collagenase (mmp-1) and stromelysin 1 (mmp-3) in human synovial fibroblasts","volume":"41","author":"Borghaei","year":"1998","journal-title":"Arthritis Rheum."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1111\/j.1365-2249.2006.03295.x","article-title":"Effect of interleukin-4 on vascular endothelial growth factor production in rheumatoid synovial fibroblasts","volume":"147","author":"Hong","year":"2007","journal-title":"Clin. Exp. Immunol."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"3803","DOI":"10.1073\/pnas.86.10.3803","article-title":"Potential antiinflammatory effects of interleukin 4: Suppression of human monocyte tumor necrosis factor alpha, interleukin 1, and prostaglandin E2","volume":"86","author":"Hart","year":"1989","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1002\/art.1780380805","article-title":"Differential effects of interleukins 10 and 4 on the production of interleukin-6 by blood and synovium monocytes in rheumatoid arthritis","volume":"38","author":"Chomarat","year":"1995","journal-title":"Arthritis Rheum."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1006\/clin.1993.1009","article-title":"Suppressive effect of interleukin-4 (IL-4) on IL-6 production by adherent rheumatoid synovial cells","volume":"66","author":"Suzuki","year":"1993","journal-title":"Clin. Immunol. Immunopathol."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"1715","DOI":"10.1002\/art.1780371202","article-title":"Interleukin-4 inhibits bone resorption through an effect on osteoclasts and proinflammatory cytokines in an ex vivo model of bone resorption in rheumatoid arthritis","volume":"37","author":"Miossec","year":"1994","journal-title":"Arthritis Rheum."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1002\/art.1780390516","article-title":"Prevention and reversal of cartilage degradation in rheumatoid arthritis by interleukin-10 and interleukin-4","volume":"39","author":"Lafeber","year":"1996","journal-title":"Arthritis Rheum."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1007\/s100670070029","article-title":"Significance of Low mRNA Levels of Interleukin-4 and -10 in Mono-nuclear Cells of the Synovial Fluid of Patients with Rheumatoid Arthritis","volume":"19","author":"Miyata","year":"2000","journal-title":"Clin. Rheumatol."},{"key":"ref_142","first-page":"1","article-title":"IL4-10 fusion protein: A novel immunoregulatory drug combining activities of interleukin 4 and interleukin 10","volume":"195","author":"Hartgring","year":"2019","journal-title":"Clin. Exp. Immunol."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"e000287","DOI":"10.1136\/rmdopen-2016-000287","article-title":"Long-term study of the impact of methotrexate on serum cytokines and lymphocyte subsets in patients with active rheumatoid arthritis: Correlation with pharmacokinetic measures","volume":"2","author":"Kremer","year":"2016","journal-title":"RMD Open"},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"758","DOI":"10.4049\/jimmunol.156.2.758","article-title":"IL-13 and IL-4 inhibit bone resorption by suppressing cyclooxygenase-2-dependent prostaglandin synthesis in osteoblasts","volume":"156","author":"Onoe","year":"1996","journal-title":"J. Immunol."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"2414","DOI":"10.1074\/jbc.M510160200","article-title":"Inhibition of hormone and cytokine-stimulated osteoclastogenesis and bone resorption by interleukin-4 and interleukin-13 is associated with increased osteoprotegerin and decreased RANKL and RANK in a STAT6-dependent pathway","volume":"281","author":"Palmqvist","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1111\/j.1365-2567.2006.02538.x","article-title":"Interleukin\u22124 inhibition of osteoclast differentiation is stronger than that of interleukin\u221213 and they are equivalent for induction of osteoprotegerin production from osteoblasts","volume":"120","author":"Yamada","year":"2007","journal-title":"Immunology"},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1359\/jbmr.080203","article-title":"Interleukin-4 and interleukin-13 stimulate the osteoclast inhibitor osteoprotegerin by human endothelial cells through the STAT6 pathway","volume":"23","author":"Stein","year":"2008","journal-title":"J. Bone Miner. Res."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"e73","DOI":"10.1016\/j.jss.2012.04.016","article-title":"Inhibitory effects of recombinant IL-4 and recombinant IL-13 on UHMWPE-induced bone destruction in the murine air pouch model","volume":"180","author":"Wang","year":"2013","journal-title":"J. Surg. Res."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"2399","DOI":"10.1002\/eji.1830261020","article-title":"Attenuation of collagen-induced arthritis in mice by treatment with vector cells engineered to secrete interleukin-13","volume":"26","author":"Bessis","year":"1996","journal-title":"Eur. J. Immunol."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1046\/j.1365-2249.1998.00500.x","article-title":"Modulation of proinflammatory cytokine production in tumour necrosis factor-alpha (TNF-alpha)-transgenic mice by treatment with cells engineered to secrete IL-4, IL-10 or IL-13","volume":"111","author":"Bessis","year":"1998","journal-title":"Clin. Exp. Immunol."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1046\/j.1365-2249.1999.00959.x","article-title":"Encapsulation in hollow fibres of xenogeneic cells engineered to secrete IL-4 or IL-13 ameliorates murine collagen-induced arthritis (CIA)","volume":"117","author":"Bessis","year":"1999","journal-title":"Clin. Exp. Immunol."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"36002","DOI":"10.1038\/srep36002","article-title":"IL-25 attenuates rheumatoid arthritis through suppression of Th17 immune responses in an IL-13-dependent manner","volume":"6","author":"Liu","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1089\/10430340252792512","article-title":"Interleukin-13 gene therapy reduces inflammation, vascularization, and bony destruction in rat adjuvant-induced arthritis","volume":"13","author":"Woods","year":"2002","journal-title":"Hum. Gene Ther."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"2535","DOI":"10.1002\/art.22823","article-title":"In vivo inhibition of angiogenesis by interleukin-13 gene therapy in a rat model of rheumatoid arthritis","volume":"56","author":"Haas","year":"2007","journal-title":"Arthritis Rheum."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"R392","DOI":"10.1186\/ar1502","article-title":"Local IL-13 gene transfer prior to immune-complex arthritis inhibits chondrocyte death and matrix-metalloproteinase-mediated cartilage matrix degradation despite enhanced joint inflammation","volume":"7","author":"Nabbe","year":"2005","journal-title":"Arthritis Res. Ther."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"11596","DOI":"10.1038\/ncomms11596","article-title":"Th2 and eosinophil responses suppress inflammatory arthritis","volume":"7","author":"Chen","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"5687","DOI":"10.4049\/jimmunol.159.11.5687","article-title":"Suppression of collagen-induced arthritis by continuous administration of IL-4","volume":"159","author":"Horsfall","year":"1997","journal-title":"J. Immunol."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1186\/ar14","article-title":"Protection against cartilage and bone destruction by systemic interleukin-4 treatment in established murine type II collagen-induced arthritis","volume":"1","author":"Joosten","year":"1999","journal-title":"Arthritis Res."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"4546","DOI":"10.4049\/jimmunol.163.8.4546","article-title":"Adenoviral vector-mediated overexpression of IL-4 in the knee joint of mice with collagen-induced arthritis prevents cartilage destruction","volume":"163","author":"Lubberts","year":"1999","journal-title":"J. Immunol."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"5383","DOI":"10.4049\/jimmunol.163.10.5383","article-title":"Proteoglycan (aggrecan)-induced arthritis in BALB\/c mice is a Th1-type disease regulated by Th2 cytokines","volume":"163","author":"Finnegan","year":"1999","journal-title":"J. Immunol."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"3345","DOI":"10.4049\/jimmunol.169.6.3345","article-title":"IL-4 and IL-12 regulate proteoglycan-induced arthritis through Stat-dependent mechanisms","volume":"169","author":"Finnegan","year":"2002","journal-title":"J. Immunol."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1002\/art.22422","article-title":"Interleukin-4 regulates proteoglycan-induced arthritis by specifically suppressing the innate immune response","volume":"56","author":"Cao","year":"2007","journal-title":"Arthritis Rheum."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"1275","DOI":"10.1172\/JCI11490","article-title":"Dendritic cells genetically engineered to express IL-4 inhibit murine collagen-induced arthritis","volume":"107","author":"Morita","year":"2001","journal-title":"J. Clin. Investig."},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1002\/art.22311","article-title":"Interleukin-17 as a molecular target in immune-mediated arthritis: Immunoregulatory properties of genetically modified murine dendritic cells that secrete interleukin-4","volume":"56","author":"Sarkar","year":"2007","journal-title":"Arthritis Rheum."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"2402","DOI":"10.1002\/art.22034","article-title":"Inhibition of angiogenesis by interleukin-4 gene therapy in rat adjuvant-induced arthritis","volume":"54","author":"Haas","year":"2006","journal-title":"Arthritis Rheum."},{"key":"ref_166","doi-asserted-by":"crossref","unstructured":"Haikal, S.M., Abdeltawab, N.F., Rashed, L.A., Abd El-Galil, T.I., Elmalt, H.A., and Amin, M.A. (2019). Combination Therapy of Mesenchymal Stromal Cells and Interleukin-4 Attenuates Rheumatoid Arthritis in a Collagen-Induced Murine Model. Cells, 8.","DOI":"10.3390\/cells8080823"},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1006\/cimm.1998.1328","article-title":"Effect of a monoclonal antibody against interleukin-4 on suppression of antigen-induced arthritis in mice by oral administration of the inducing antigen","volume":"187","author":"Yoshino","year":"1998","journal-title":"Cell Immunol."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1053\/joca.2001.0501","article-title":"Local overexpression of adeno-viral IL-4 protects cartilage from metallo proteinase-induced destruction during immune complex-mediated arthritis by preventing activation of pro-MMPs","volume":"10","author":"Holthuysen","year":"2002","journal-title":"Osteoarthr. Cartil."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"1866","DOI":"10.1002\/art.21104","article-title":"Interleukin-4 can be a key positive regulator of inflammatory arthritis","volume":"52","author":"Ohmura","year":"2005","journal-title":"Arthritis Rheum."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"2944","DOI":"10.1002\/1521-4141(2002010)32:10<2944::AID-IMMU2944>3.0.CO;2-4","article-title":"IL-4-deficient mice develop less acute but more chronic relapsing collagen-induced arthritis","volume":"32","author":"Svensson","year":"2002","journal-title":"Eur. J. Immunol."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1046\/j.1365-2567.1998.00457.x","article-title":"Interleukin-4 and interleukin-10 are chondroprotective and decrease mononuclear cell recruitment in human rheumatoid synovium in vivo","volume":"93","author":"Jorgensen","year":"1998","journal-title":"Immunology"},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1046\/j.1365-2141.2001.02525.x","article-title":"Interleukin 4 therapy for patients with chronic lymphocytic leukaemia: A phase I\/II study","volume":"112","author":"Lundin","year":"2001","journal-title":"Br. J. Haematol."},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1093\/oxfordjournals.annonc.a058878","article-title":"A phase I trial of continuous infusion interleukin-4 (IL-4) alone and following interleukin-2 (IL-2) in cancer patients","volume":"5","author":"Sosman","year":"1994","journal-title":"Ann. Oncol."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"1629","DOI":"10.1002\/1097-0142(19951101)76:9<1629::AID-CNCR2820760920>3.0.CO;2-Q","article-title":"A phase II study of sub-cutaneous recombinant human interleukin-4 in metastatic renal cellcarcinoma","volume":"76","author":"Stadler","year":"1995","journal-title":"Cancer"},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1097\/00002371-199811000-00006","article-title":"Phase II trial of recombinant human interleukin-4 in patients with disseminated malignant melanoma: A Southwest Oncology Group study","volume":"21","author":"Whitehead","year":"1998","journal-title":"J. Immunother."},{"key":"ref_176","first-page":"46","article-title":"A phase II study of recombinant human interleukin-4 for advanced or recurrent non-small cell lung cancer","volume":"4","author":"Vokes","year":"1998","journal-title":"Cancer J. Sci. Am."},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1038\/nm804","article-title":"Interleukin-4 therapy of psoriasis induces Th2 responses and improves human autoimmune disease","volume":"9","author":"Ghoreschi","year":"2003","journal-title":"Nat. Med."},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1016\/j.tips.2003.10.006","article-title":"Interleukin 4 treatment of psoriasis: Are pleiotropic cytokines suitable therapies for autoimmune diseases?","volume":"24","author":"Martin","year":"2003","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1517\/17460441.3.3.357","article-title":"Interleukin 4 as a potential drug candidate for psoriasis","volume":"3","author":"Weigert","year":"2008","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1002\/jps.24243","article-title":"Formulation and stability of cytokine therapeutics","volume":"104","author":"Peltoniemi","year":"2015","journal-title":"J. Pharm. Sci."},{"key":"ref_181","first-page":"8","article-title":"Engineering Strategies for Immunomodulatory Cytokine Therapies\/; Challenges and Clinical Progress","volume":"4","author":"Pires","year":"2021","journal-title":"Adv. Ther."},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"426","DOI":"10.3390\/antib2030426","article-title":"Molecular Engineering of Therapeutic Cytokines","volume":"2","author":"Roome","year":"2013","journal-title":"Antibodies"},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"990","DOI":"10.1038\/nchembio.1096","article-title":"Redirecting cell-type specific cytokine responses with engineered interleukin-4 superkines","volume":"8","author":"Junttila","year":"2012","journal-title":"Nat. Chem. Biol."},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"7353","DOI":"10.1523\/JNEUROSCI.0092-16.2016","article-title":"IL4-10 fusion protein is a novel drug to treat persistent inflammatory pain","volume":"36","author":"Eijkelkamp","year":"2016","journal-title":"J. Neurosci."},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1016\/j.joca.2018.05.005","article-title":"Il4-10 fusion protein has chondroprotective, anti-inflammatory and potentially analgesic effects in the treatment of osteoarthritis","volume":"26","author":"Mastbergen","year":"2018","journal-title":"Osteoarthr. Cartil."},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"887","DOI":"10.3390\/ijms16010887","article-title":"Cytokine-Modulating Strategies and Newer Cytokine Targets for Arthritis Therapy","volume":"16","author":"Venkatesha","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_187","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1080\/08820139.2020.1752713","article-title":"Cytokine-Encapsulated Biodegradable Microspheres for Immune Therapy","volume":"49","author":"Egilmez","year":"2020","journal-title":"Immunol. Investig."},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1039\/C9NH00291J","article-title":"Biomimetic nanoparticle technology for cardiovascular disease detection and treatment","volume":"5","author":"Park","year":"2020","journal-title":"Nanoscale Horiz."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/11\/3000\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:25:28Z","timestamp":1760167528000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/11\/3000"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,3]]},"references-count":188,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["cells10113000"],"URL":"https:\/\/doi.org\/10.3390\/cells10113000","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,3]]}}}