{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T07:26:18Z","timestamp":1793863578246,"version":"4.6.1"},"reference-count":58,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,5,17]],"date-time":"2019-05-17T00:00:00Z","timestamp":1558051200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,5,17]],"date-time":"2019-05-17T00:00:00Z","timestamp":1558051200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Psoriasis is a chronic, recurrent, immune-mediated, hyperproliferative inflammatory skin disease. The role of the adaptive immune system, particularly of Th1 and Th17 lymphocytes, has been regarded as prominent in the immunopathogenesis of psoriasis, as well as decreased Tregs function. Immunobiological drugs were administered in therapeutic pulses and a few studies evaluate their effects on the immune repertoire. The aim of this study was to evaluate the adaptive immune profile of patients with severe psoriasis under immunobiological treatment in two time points. Thirty-two psoriasis patients and 10 control patients were evaluated. In the group of psoriasis patients, 10 patients were on anti-TNF and 14 patients on methotrexate treatment, while 8 individuals were not treated. IL-17, IFN-\u03b3, TNF-\u03b1, IL-6, IL-2, and IL-10 were analyzed. CD4 T cell intracellular cytokines were analyzed. It was observed that stimulation could significantly increase the production of IL-17, IFN-\u03b3, TNF-\u03b1, and IL-10 only before anti-TNF pulse therapy. The activation of Th1 and Treg cells after stimulation was significantly higher before anti-TNF pulse. Patients on methotrexate or anti-TNF therapy produced significantly lower levels of TNF-\u03b1, IL-10, and IL-6. Furthermore, these patients showed a significant decrease in the activated CD4+ T cells. The treatment with immunomodulator or methotrexate modulates the activation of CD4+ T cells, and anti-TNF treatment appears to have a modulating effect on the activation and production of Th1, Th17, and Treg cells.<\/jats:p>","DOI":"10.1038\/s41598-019-43899-9","type":"journal-article","created":{"date-parts":[[2019,5,17]],"date-time":"2019-05-17T10:04:37Z","timestamp":1558087477000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":81,"title":["Th1, Th17, and Treg Responses are Differently Modulated by TNF-\u03b1 Inhibitors and Methotrexate in Psoriasis Patients"],"prefix":"10.1038","volume":"9","author":[{"given":"Sandro C.","family":"Furiati","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6542-7406","authenticated-orcid":false,"given":"Jonatas S.","family":"Catarino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2966-7621","authenticated-orcid":false,"given":"Marcos V.","family":"Silva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafaela F.","family":"Silva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rayane B.","family":"Estevam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reginaldo B.","family":"Teodoro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanivia L.","family":"Pereira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meire","family":"Ataide","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"Virmondes","family":"Rodrigues","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denise B. R.","family":"Rodrigues","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,5,17]]},"reference":[{"key":"43899_CR1","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1111\/jdv.13854","volume":"31","author":"IM Michalek","year":"2017","unstructured":"Michalek, I. M., Loring, B. & John, S. M. A systematic review of worldwide epidemiology of psoriasis. J Eur Acad Dermatol Venereol 31, 205\u2013212, https:\/\/doi.org\/10.1111\/jdv.13854 (2017).","journal-title":"J Eur Acad Dermatol Venereol"},{"key":"43899_CR2","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1038\/jid.2012.339","volume":"133","author":"R Parisi","year":"2013","unstructured":"Parisi, R. et al. Global epidemiology of psoriasis: a systematic review of incidence and prevalence. The Journal of investigative dermatology 133, 377\u2013385, https:\/\/doi.org\/10.1038\/jid.2012.339 (2013).","journal-title":"The Journal of investigative dermatology"},{"key":"43899_CR3","doi-asserted-by":"publisher","first-page":"680","DOI":"10.1111\/j.1468-3083.2012.04531.x","volume":"27","author":"XT Lima","year":"2013","unstructured":"Lima, X. T., Minnillo, R., Spencer, J. M. & Kimball, A. B. Psoriasis prevalence among the 2009 AAD National Melanoma\/Skin Cancer Screening Program participants. J Eur Acad Dermatol Venereol 27, 680\u2013685, https:\/\/doi.org\/10.1111\/j.1468-3083.2012.04531.x (2013).","journal-title":"J Eur Acad Dermatol Venereol"},{"key":"43899_CR4","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/j.cytogfr.2014.10.009","volume":"26","author":"L Grine","year":"2015","unstructured":"Grine, L., Dejager, L., Libert, C. & Vandenbroucke, R. E. An inflammatory triangle in psoriasis: TNF, type I IFNs and IL-17. Cytokine & growth factor reviews 26, 25\u201333, https:\/\/doi.org\/10.1016\/j.cytogfr.2014.10.009 (2015).","journal-title":"Cytokine & growth factor reviews"},{"key":"43899_CR5","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1016\/S0140-6736(07)61128-3","volume":"370","author":"CEM Griffiths","year":"2007","unstructured":"Griffiths, C. E. M. & Barker, J. Pathogenesis and clinical features of psoriasis. The Lancet 370, 263\u2013271, https:\/\/doi.org\/10.1016\/S0140-6736(07)61128-3 (2007).","journal-title":"The Lancet"},{"key":"43899_CR6","doi-asserted-by":"publisher","first-page":"829","DOI":"10.3899\/jrheum.140474","volume":"42","author":"R Ranza","year":"2015","unstructured":"Ranza, R. et al. Prevalence of Psoriatic Arthritis in a Large Cohort of Brazilian Patients with Psoriasis. The Journal of Rheumatology 42, 829\u2013834, https:\/\/doi.org\/10.3899\/jrheum.140474 (2015).","journal-title":"The Journal of Rheumatology"},{"key":"43899_CR7","doi-asserted-by":"publisher","first-page":"1207","DOI":"10.1038\/sj.jid.5701213","volume":"128","author":"MA Lowes","year":"2008","unstructured":"Lowes, M. A. et al. Psoriasis vulgaris lesions contain discrete populations of Th1 and Th17 T cells. The Journal of investigative dermatology 128, 1207\u20131211, https:\/\/doi.org\/10.1038\/sj.jid.5701213 (2008).","journal-title":"The Journal of investigative dermatology"},{"key":"43899_CR8","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.jaad.2005.07.073","volume":"57","author":"MM Jiaravuthisan","year":"2007","unstructured":"Jiaravuthisan, M. M., Sasseville, D., Vender, R. B., Murphy, F. & Muhn, C. Y. Psoriasis of the nail: Anatomy, pathology, clinical presentation, and a review of the literature on therapy. Journal of the American Academy of Dermatology 57, 1\u201327, https:\/\/doi.org\/10.1016\/j.jaad.2005.07.073 (2007).","journal-title":"Journal of the American Academy of Dermatology"},{"key":"43899_CR9","doi-asserted-by":"publisher","first-page":"679","DOI":"10.1038\/nri2622","volume":"9","author":"FO Nestle","year":"2009","unstructured":"Nestle, F. O., Di Meglio, P., Qin, J.-Z. Z. & Nickoloff, B. J. Skin immune sentinels in health and disease. Nature reviews. Immunology 9, 679\u2013691, https:\/\/doi.org\/10.1038\/nri2622 (2009).","journal-title":"Nature reviews. Immunology"},{"key":"43899_CR10","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1084\/jem.20050500","volume":"202","author":"FO Nestle","year":"2005","unstructured":"Nestle, F. O. et al. Plasmacytoid predendritic cells initiate psoriasis through interferon-alpha production. The Journal of experimental medicine 202, 135\u2013143, https:\/\/doi.org\/10.1084\/jem.20050500 (2005).","journal-title":"The Journal of experimental medicine"},{"key":"43899_CR11","doi-asserted-by":"publisher","first-page":"1983","DOI":"10.1084\/jem.20090480","volume":"206","author":"D Ganguly","year":"2009","unstructured":"Ganguly, D. et al. Self-RNA-antimicrobial peptide complexes activate human dendritic cells through TLR7 and TLR8. The Journal of experimental medicine 206, 1983\u20131994, https:\/\/doi.org\/10.1084\/jem.20090480 (2009).","journal-title":"The Journal of experimental medicine"},{"key":"43899_CR12","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1016\/j.imlet.2017.04.005","volume":"189","author":"A Khasawneh","year":"2017","unstructured":"Khasawneh, A. et al. Myeloid but not plasmacytoid blood DCs possess Th1 polarizing and Th1\/Th17 recruiting capacity in psoriasis. Immunol Lett 189, 109\u2013113, https:\/\/doi.org\/10.1016\/j.imlet.2017.04.005 (2017).","journal-title":"Immunol Lett"},{"issue":"4","key":"43899_CR13","doi-asserted-by":"publisher","first-page":"302","DOI":"10.1038\/cmi.2012.15","volume":"9","author":"Yihua Cai","year":"2012","unstructured":"Cai, Y., Fleming, C. & Yan, J. New insights of T cells in the pathogenesis of psoriasis. Cellular & Molecular Immunology 9, https:\/\/doi.org\/10.1038\/cmi.2012.15 (2012).","journal-title":"Cellular & Molecular Immunology"},{"key":"43899_CR14","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1146\/annurev.immunol.021908.132710","volume":"27","author":"T Korn","year":"2009","unstructured":"Korn, T., Bettelli, E., Oukka, M. & Kuchroo, V. K. IL-17 and Th17 Cells. Immunology 27, 485\u2013517, https:\/\/doi.org\/10.1146\/annurev.immunol.021908.132710 (2009).","journal-title":"Immunology"},{"key":"43899_CR15","doi-asserted-by":"publisher","first-page":"752","DOI":"10.1046\/j.1523-1747.1999.00749.x","volume":"113","author":"LM Austin","year":"1999","unstructured":"Austin, L. M., Ozawa, M., Kikuchi, T., Walters, I. B. & Krueger, J. G. The majority of epidermal T cells in Psoriasis vulgaris lesions can produce type 1 cytokines, interferon-gamma, interleukin-2, and tumor necrosis factor-alpha, defining TC1 (cytotoxic T lymphocyte) and TH1 effector populations: a type 1 differentiation bias is also measured in circulating blood T cells in psoriatic patients. J Invest Dermatol 113, 752\u2013759, https:\/\/doi.org\/10.1046\/j.1523-1747.1999.00749.x (1999).","journal-title":"J Invest Dermatol"},{"key":"43899_CR16","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1111\/j.1365-2249.2007.03511.x","volume":"150","author":"K Boniface","year":"2007","unstructured":"Boniface, K. et al. A role for T cell-derived interleukin 22 in psoriatic skin inflammation. Clinical & Experimental Immunology 150, 407\u2013415, https:\/\/doi.org\/10.1111\/j.1365-2249.2007.03511.x (2007).","journal-title":"Clinical & Experimental Immunology"},{"key":"43899_CR17","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1111\/bjd.12631","volume":"170","author":"E Christophers","year":"2014","unstructured":"Christophers, E., Metzler, G. & R\u00f6cken, M. Bimodal immune activation in psoriasis. British Journal of Dermatology 170, 59\u201365, https:\/\/doi.org\/10.1111\/bjd.12631 (2014).","journal-title":"British Journal of Dermatology"},{"key":"43899_CR18","doi-asserted-by":"publisher","first-page":"179","DOI":"10.3390\/ijms19010179","volume":"19","author":"A Chiricozzi","year":"2018","unstructured":"Chiricozzi, A., Romanelli, P., Volpe, E., Borsellino, G. & Romanelli, M. Scanning the Immunopathogenesis of Psoriasis. International Journal of Molecular Sciences 19, 179, https:\/\/doi.org\/10.3390\/ijms19010179 (2018).","journal-title":"International Journal of Molecular Sciences"},{"key":"43899_CR19","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1007\/s40259-015-0144-3","volume":"29","author":"M Gooderham","year":"2015","unstructured":"Gooderham, M. & Papp, K. Selective Phosphodiesterase Inhibitors for Psoriasis: Focus on Apremilast. BioDrugs 29, 327\u2013339, https:\/\/doi.org\/10.1007\/s40259-015-0144-3 (2015).","journal-title":"BioDrugs"},{"key":"43899_CR20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.5070\/D33N39N8XM","volume":"18","author":"P Mudigonda","year":"2012","unstructured":"Mudigonda, P. et al. Interleukin-23 and interleukin-17: importance in pathogenesis and therapy of psoriasis. Dermatology online journal 18, 1 (2012).","journal-title":"Dermatology online journal"},{"key":"43899_CR21","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1159\/000353398","volume":"227","author":"C Mattozzi","year":"2013","unstructured":"Mattozzi, C. et al. Importance of regulatory T cells in the pathogenesis of psoriasis: review of the literature. Dermatology (Basel, Switzerland) 227, 134\u2013145, https:\/\/doi.org\/10.1159\/000353398 (2013).","journal-title":"Dermatology (Basel, Switzerland)"},{"key":"43899_CR22","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1016\/j.jdermsci.2015.11.007","volume":"81","author":"L Yang","year":"2016","unstructured":"Yang, L. et al. Impaired function of regulatory T cells in patients with psoriasis is mediated by phosphorylation of STAT3. Journal of dermatological science 81, 85\u201392, https:\/\/doi.org\/10.1016\/j.jdermsci.2015.11.007 (2016).","journal-title":"Journal of dermatological science"},{"key":"43899_CR23","doi-asserted-by":"publisher","first-page":"1785","DOI":"10.1038\/jid.2011.200","volume":"131","author":"DC Soler","year":"2011","unstructured":"Soler, D. C. & McCormick, T. S. The Dark Side of Regulatory T Cells in Psoriasis. Journal of Investigative Dermatology 131, 1785\u20131786, https:\/\/doi.org\/10.1038\/jid.2011.200 (2011).","journal-title":"Journal of Investigative Dermatology"},{"key":"43899_CR24","doi-asserted-by":"publisher","first-page":"4620","DOI":"10.4049\/jimmunol.0903329","volume":"184","author":"R Gandhi","year":"2010","unstructured":"Gandhi, R. et al. Cutting edge: human latency-associated peptide+ T cells: a novel regulatory T cell subset. Journal of immunology 184, 4620\u20134624, https:\/\/doi.org\/10.4049\/jimmunol.0903329 (2010).","journal-title":"Journal of immunology"},{"key":"43899_CR25","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1093\/jmcb\/mjr033","volume":"4","author":"DQ Tran","year":"2012","unstructured":"Tran, D. Q. TGF-beta: the sword, the wand, and the shield of FOXP3(+) regulatory T cells. Journal of molecular cell biology 4, 29\u201337, https:\/\/doi.org\/10.1093\/jmcb\/mjr033 (2012).","journal-title":"Journal of molecular cell biology"},{"key":"43899_CR26","doi-asserted-by":"publisher","first-page":"430943","DOI":"10.1155\/2015\/430943","volume":"2015","author":"L Islas-Vazquez","year":"2015","unstructured":"Islas-Vazquez, L. et al. LAP TGF-Beta Subset of CD4(+)CD25(+)CD127(\u2212) Treg Cells is Increased and Overexpresses LAP TGF-Beta in Lung Adenocarcinoma Patients. BioMed research international 2015, 430943, https:\/\/doi.org\/10.1155\/2015\/430943 (2015).","journal-title":"BioMed research international"},{"key":"43899_CR27","doi-asserted-by":"publisher","first-page":"e108554","DOI":"10.1371\/journal.pone.0108554","volume":"9","author":"J Mahalingam","year":"2014","unstructured":"Mahalingam, J. et al. CD4(+) T cells expressing latency-associated peptide and Foxp3 are an activated subgroup of regulatory T cells enriched in patients with colorectal cancer. PLoS One 9, e108554, https:\/\/doi.org\/10.1371\/journal.pone.0108554 (2014).","journal-title":"PLoS One"},{"key":"43899_CR28","doi-asserted-by":"publisher","first-page":"3183","DOI":"10.1084\/jem.20071094","volume":"204","author":"LC Zaba","year":"2007","unstructured":"Zaba, L. C. et al. Amelioration of epidermal hyperplasia by TNF inhibition is associated with reduced Th17 responses. The Journal of experimental medicine 204, 3183\u20133194, https:\/\/doi.org\/10.1084\/jem.20071094 (2007).","journal-title":"The Journal of experimental medicine"},{"key":"43899_CR29","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1007\/s00281-015-0539-8","volume":"38","author":"SK Mahil","year":"2016","unstructured":"Mahil, S. K., Capon, F. & Barker, J. N. Update on psoriasis immunopathogenesis and targeted immunotherapy. Seminars in immunopathology 38, 11\u201327, https:\/\/doi.org\/10.1007\/s00281-015-0539-8 (2016).","journal-title":"Seminars in immunopathology"},{"key":"43899_CR30","doi-asserted-by":"publisher","first-page":"1951","DOI":"10.1002\/art.1780391203","volume":"39","author":"BN Cronstein","year":"1996","unstructured":"Cronstein, B. N. Molecular therapeutics. Methotrexate and its mechanism of action. Arthritis and rheumatism 39, 1951\u20131960 (1996).","journal-title":"Arthritis and rheumatism"},{"key":"43899_CR31","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1016\/j.cca.2015.10.020","volume":"451","author":"T Elango","year":"2015","unstructured":"Elango, T., Thirupathi, A., Subramanian, S., Dayalan, H. & Gnanaraj, P. Methotrexate normalized keratinocyte activation cycle by overturning abnormal keratins as well as deregulated inflammatory mediators in psoriatic patients. Clinica Chimica Acta 451, 329\u2013337, https:\/\/doi.org\/10.1016\/j.cca.2015.10.020 (2015).","journal-title":"Clinica Chimica Acta"},{"key":"43899_CR32","doi-asserted-by":"publisher","first-page":"2046","DOI":"10.1111\/jdv.14406","volume":"31","author":"E Sbidian","year":"2017","unstructured":"Sbidian, E. et al. Factors associated with the choice of the first biologic in psoriasis: real-life analysis from the Psobioteq cohort. Journal of the European Academy of Dermatology and Venereology 31, 2046\u20132054, https:\/\/doi.org\/10.1111\/jdv.14406 (2017).","journal-title":"Journal of the European Academy of Dermatology and Venereology"},{"key":"43899_CR33","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1590\/S0365-05962010000100002","volume":"85","author":"AL Bressan","year":"2010","unstructured":"Bressan, A. L., Silva, R. S., Fontenelle, E. & Gripp, A. C. Immunosuppressive agents in Dermatology. Anais brasileiros de dermatologia 85, 9\u201322 (2010).","journal-title":"Anais brasileiros de dermatologia"},{"key":"43899_CR34","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1038\/JID.2015.378","volume":"136","author":"J Kim","year":"2016","unstructured":"Kim, J. et al. Molecular Phenotyping Small (Asian) versus Large (Western) Plaque Psoriasis Shows Common Activation of IL-17 Pathway Genes but Different Regulatory Gene Sets. The Journal of investigative dermatology 136, 161\u2013172, https:\/\/doi.org\/10.1038\/JID.2015.378 (2016).","journal-title":"The Journal of investigative dermatology"},{"key":"43899_CR35","doi-asserted-by":"publisher","first-page":"1215","DOI":"10.1093\/rheumatology\/keq031","volume":"49","author":"T Horiuchi","year":"2010","unstructured":"Horiuchi, T., Mitoma, H., Harashima, S.-I., Tsukamoto, H. & Shimoda, T. Transmembrane TNF-\u03b1: structure, function and interaction with anti-TNF agents. Rheumatology 49, 1215\u20131228, https:\/\/doi.org\/10.1093\/rheumatology\/keq031 (2010).","journal-title":"Rheumatology"},{"key":"43899_CR36","doi-asserted-by":"publisher","first-page":"1256","DOI":"10.1016\/j.imbio.2011.07.006","volume":"216","author":"O Aravena","year":"2011","unstructured":"Aravena, O. et al. Anti-TNF therapy in patients with rheumatoid arthritis decreases Th1 and Th17 cell populations and expands IFN-\u03b3-producing NK cell and regulatory T cell subsets. Immunobiology 216, 1256\u20131263, https:\/\/doi.org\/10.1016\/j.imbio.2011.07.006 (2011).","journal-title":"Immunobiology"},{"key":"43899_CR37","doi-asserted-by":"publisher","first-page":"278","DOI":"10.1016\/j.intimp.2015.11.005","volume":"29","author":"L Luan","year":"2015","unstructured":"Luan, L., Han, S., Wang, H. & Liu, X. Down-regulation of the Th1, Th17, and Th22 pathways due to anti-TNF-\u03b1 treatment in psoriasis. International Immunopharmacology 29, 278\u2013284, https:\/\/doi.org\/10.1016\/j.intimp.2015.11.005 (2015).","journal-title":"International Immunopharmacology"},{"key":"43899_CR38","doi-asserted-by":"publisher","first-page":"2297","DOI":"10.3390\/ijms18112297","volume":"18","author":"K R\u00f8nholt","year":"2017","unstructured":"R\u00f8nholt, K. & Iversen, L. Old and New Biological Therapies for Psoriasis. International Journal of Molecular Sciences 18, 2297, https:\/\/doi.org\/10.3390\/ijms18112297 (2017).","journal-title":"International Journal of Molecular Sciences"},{"key":"43899_CR39","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1016\/j.jaad.2013.12.036","volume":"71","author":"CW Lynde","year":"2014","unstructured":"Lynde, C. W., Poulin, Y., Vender, R., Bourcier, M. & Khalil, S. Interleukin 17A: Toward a new understanding of psoriasis pathogenesis. Journal of the American Academy of Dermatology 71, 141\u2013150, https:\/\/doi.org\/10.1016\/j.jaad.2013.12.036 (2014).","journal-title":"Journal of the American Academy of Dermatology"},{"key":"43899_CR40","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s13555-015-0092-3","volume":"6","author":"M Campa","year":"2016","unstructured":"Campa, M., Mansouri, B., Warren, R. & Menter, A. A Review of Biologic Therapies Targeting IL-23 and IL-17 for Use in Moderate-to-Severe Plaque Psoriasis. Dermatology and therapy 6, 1\u201312, https:\/\/doi.org\/10.1007\/s13555-015-0092-3 (2016).","journal-title":"Dermatology and therapy"},{"key":"43899_CR41","doi-asserted-by":"publisher","first-page":"4733","DOI":"10.4049\/jimmunol.181.7.4733","volume":"181","author":"I Kryczek","year":"2008","unstructured":"Kryczek, I. et al. Induction of IL-17+ T cell trafficking and development by IFN-gamma: mechanism and pathological relevance in psoriasis. Journal of immunology (Baltimore, Md.: 1950) 181, 4733\u20134741 (2008).","journal-title":"Journal of immunology (Baltimore, Md.: 1950)"},{"key":"43899_CR42","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1155\/MI.2005.273","volume":"2005","author":"O Arican","year":"2005","unstructured":"Arican, O., Aral, M., Sasmaz, S. & Ciragil, P. Serum levels of TNF-alpha, IFN-gamma, IL-6, IL-8, IL-12, IL-17, and IL-18 in patients with active psoriasis and correlation with disease severity. Mediators of inflammation 2005, 273\u2013279, https:\/\/doi.org\/10.1155\/MI.2005.273 (2005).","journal-title":"Mediators of inflammation"},{"key":"43899_CR43","doi-asserted-by":"publisher","first-page":"1293","DOI":"10.1016\/j.yexcr.2011.01.024","volume":"317","author":"KE Nograles","year":"2011","unstructured":"Nograles, K. E. & Krueger, J. G. Anti-cytokine therapies for psoriasis. Experimental cell research 317, 1293\u20131300, https:\/\/doi.org\/10.1016\/j.yexcr.2011.01.024 (2011).","journal-title":"Experimental cell research"},{"key":"43899_CR44","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1080\/09629350310001619753","volume":"12","author":"SE Jacob","year":"2003","unstructured":"Jacob, S. E., Nassiri, M., Kerdel, F. A. & Vincek, V. Simultaneous measurement of multiple Th1 and Th2 serum cytokines in psoriasis and correlation with disease severity. Mediators of inflammation 12, 309\u2013313, https:\/\/doi.org\/10.1080\/09629350310001619753 (2003).","journal-title":"Mediators of inflammation"},{"key":"43899_CR45","doi-asserted-by":"publisher","first-page":"1331","DOI":"10.1111\/j.1468-3083.2012.04492.x","volume":"26","author":"TC Lucka","year":"2012","unstructured":"Lucka, T. C. et al. Efficacy of systemic therapies for moderate-to-severe psoriasis: a systematic review and meta-analysis of long-term treatment. Journal of the European Academy of Dermatology and Venereology: JEADV 26, 1331\u20131344, https:\/\/doi.org\/10.1111\/j.1468-3083.2012.04492.x (2012).","journal-title":"Journal of the European Academy of Dermatology and Venereology: JEADV"},{"key":"43899_CR46","doi-asserted-by":"publisher","first-page":"2721","DOI":"10.4049\/jimmunol.175.4.2721","volume":"175","author":"AB Gottlieb","year":"2005","unstructured":"Gottlieb, A. B. et al. TNF inhibition rapidly down-regulates multiple proinflammatory pathways in psoriasis plaques. Journal of immunology (Baltimore, Md.: 1950) 175, 2721\u20132729 (2005).","journal-title":"Journal of immunology (Baltimore, Md.: 1950)"},{"key":"43899_CR47","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2017\/6104054","volume":"2017","author":"JM Rojas","year":"2017","unstructured":"Rojas, J. M., Avia, M., Mart\u00edn, V. & Sevilla, N. IL-10: A Multifunctional Cytokine in Viral Infections. Journal of Immunology Research 2017, 1\u201314, https:\/\/doi.org\/10.1155\/2017\/6104054 (2017).","journal-title":"Journal of Immunology Research"},{"key":"43899_CR48","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1146\/annurev-immunol-031210-101312","volume":"29","author":"W Ouyang","year":"2011","unstructured":"Ouyang, W., Rutz, S., Crellin, N. K., Valdez, P. A. & Hymowitz, S. G. Regulation and functions of the IL-10 family of cytokines in inflammation and disease. Annual review of immunology 29, 71\u2013109, https:\/\/doi.org\/10.1146\/annurev-immunol-031210-101312 (2011).","journal-title":"Annual review of immunology"},{"key":"43899_CR49","first-page":"53","volume":"2","author":"AA Al-Robaee","year":"2008","unstructured":"Al-Robaee, A. A., Al-Zolibani, A. A., Al-Shobili, H. A., Kazamel, A. & Settin, A. IL-10 implications in psoriasis. International journal of health sciences 2, 53\u201358 (2008).","journal-title":"International journal of health sciences"},{"key":"43899_CR50","first-page":"86","volume":"21","author":"J Cheng","year":"2001","unstructured":"Cheng, J. et al. A study on the expression of interleukin (IL)-10 and IL-12 P35, P40 mRNA in the psoriatic lesions. Journal of Tongji Medical University\u2009=\u2009Tong ji yi ke da xue xue bao 21, 86\u201388 (2001).","journal-title":"Journal of Tongji Medical University\u2009=\u2009Tong ji yi ke da xue xue bao"},{"issue":"3","key":"43899_CR51","doi-asserted-by":"publisher","first-page":"e0194430","DOI":"10.1371\/journal.pone.0194430","volume":"13","author":"Djalma A. Alves da Silva","year":"2018","unstructured":"da Silva, D. A. et al. TNF-\u03b1 blockade impairs in vitro tuberculous granuloma formation and down modulate Th1, Th17 and Treg cytokines. PLOS One 13, https:\/\/doi.org\/10.1371\/journal.pone.0194430 (2018).","journal-title":"PLOS ONE"},{"key":"43899_CR52","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1684\/ejd.2011.1362","volume":"21","author":"AG Richetta","year":"2011","unstructured":"Richetta, A. G. et al. CD4+ CD25+ T-regulatory cells in psoriasis. Correlation between their numbers and biologics-induced clinical improvement. European journal of dermatology: EJD 21, 344\u2013348, https:\/\/doi.org\/10.1684\/ejd.2011.1362 (2011).","journal-title":"European journal of dermatology: EJD"},{"key":"43899_CR53","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1016\/j.clim.2009.11.008","volume":"135","author":"L Zhang","year":"2010","unstructured":"Zhang, L., Yang, X.-Q. Q., Cheng, J., Hui, R.-S. S. & Gao, T.-W. W. Increased Th17 cells are accompanied by FoxP3(+) Treg cell accumulation and correlated with psoriasis disease severity. Clinical immunology (Orlando, Fla.) 135, 108\u2013117, https:\/\/doi.org\/10.1016\/j.clim.2009.11.008 (2010).","journal-title":"Clinical immunology (Orlando, Fla.)"},{"key":"43899_CR54","doi-asserted-by":"publisher","first-page":"437","DOI":"10.3389\/fcimb.2017.00437","volume":"7","author":"HT Hop","year":"2017","unstructured":"Hop, H. T. et al. Activation of NF-kB-Mediated TNF-Induced Antimicrobial Immunity Is Required for the Efficient Brucella abortus Clearance in RAW 264.7 Cells. Frontiers in Cellular and Infection. Microbiology 7, 437, https:\/\/doi.org\/10.3389\/fcimb.2017.00437 (2017).","journal-title":"Microbiology"},{"key":"43899_CR55","doi-asserted-by":"publisher","first-page":"602","DOI":"10.1093\/rheumatology\/34.7.602","volume":"34","author":"M Seitz","year":"1995","unstructured":"Seitz, M. et al. Methotrexate action in rheumatoid arthritis: stimulation of cytokine inhibitor and inhibition of chemokine production by peripheral blood mononuclear cells. British journal of rheumatology 34, 602\u2013609 (1995).","journal-title":"British journal of rheumatology"},{"key":"43899_CR56","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1046\/j.1365-2249.1999.00753.x","volume":"115","author":"MF Neurath","year":"1999","unstructured":"Neurath, M. F. et al. Methotrexate specifically modulates cytokine production by T cells and macrophages in murine collagen-induced arthritis (CIA): a mechanism for methotrexate-mediated immunosuppression. Clinical and experimental immunology 115, 42\u201355 (1999).","journal-title":"Clinical and experimental immunology"},{"key":"43899_CR57","doi-asserted-by":"publisher","first-page":"315","DOI":"10.2147\/TCRM.S111107","volume":"13","author":"TL Hanley","year":"2017","unstructured":"Hanley, T. L. & Yiu, Z. Z. Role of IL-17 in plaque psoriasis: therapeutic potential of ixekizumab. Therapeutics and clinical risk management 13, 315\u2013323, https:\/\/doi.org\/10.2147\/TCRM.S111107 (2017).","journal-title":"Therapeutics and clinical risk management"},{"key":"43899_CR58","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1016\/j.jep.2017.11.020","volume":"213","author":"G Park","year":"2018","unstructured":"Park, G., Lee, S., Han, J.-Y. & Oh, D.-S. Altered TNF-\u03b1 response by Aconibal\u00ae and methotrexate in a lipopolysaccharide-induced setting of inflammatory conditions: Potential on a synergistic combination. Journal of Ethnopharmacology 213, 191\u2013197, https:\/\/doi.org\/10.1016\/j.jep.2017.11.020 (2018).","journal-title":"Journal of Ethnopharmacology"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-43899-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-43899-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-43899-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T09:48:24Z","timestamp":1671270504000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-43899-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,5,17]]},"references-count":58,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["43899"],"URL":"https:\/\/doi.org\/10.1038\/s41598-019-43899-9","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,5,17]]},"assertion":[{"value":"27 November 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 April 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 May 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"7526"}}