{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T10:14:47Z","timestamp":1785838487079,"version":"3.56.0"},"reference-count":95,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,3,24]],"date-time":"2022-03-24T00:00:00Z","timestamp":1648080000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["19-75-30032"],"award-info":[{"award-number":["19-75-30032"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012190","name":"Ministry of Science and Higher Education of the Russian Federation","doi-asserted-by":"publisher","award":["075-15-2021-106"],"award-info":[{"award-number":["075-15-2021-106"]}],"id":[{"id":"10.13039\/501100012190","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Sirius University of Science and Technology","award":["IMB-RND-2102"],"award-info":[{"award-number":["IMB-RND-2102"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Combined anti-cytokine therapy is a promising therapeutic approach for uncontrolled steroid-resistant asthma. In this regard, simultaneous blockade of IL-4 and IL-13 signaling by Dupilumab (anti-IL-4Ra monoclonal antibody) was recently approved for severe eosinophilic asthma. However, no therapeutic options for neutrophilic asthma are currently available. Recent advances in our understanding of asthma pathogenesis suggest that both IL-6 and TNF may represent potential targets for treatment of severe neutrophilic asthma. Nevertheless, the efficacy of simultaneous pharmacological inhibition of TNF and IL-6 in asthma was not yet studied. To evaluate the potency of combined cytokine inhibition, we simultaneously administrated IL-6 and TNF inhibitors to BALB\/c mice with HDM-induced asthma. Combined IL-6\/TNF inhibition, but not individual blockade of these two cytokines, led to complex anti-inflammatory effects including reduced Th2-induced eosinophilia and less prominent Th17\/Th1-mediated neutrophilic infiltrate in the airways. Taken together, our results provide evidence for therapeutic potential of combined IL-6\/TNF inhibition in severe steroid-resistant asthma.<\/jats:p>","DOI":"10.3390\/ijms23073521","type":"journal-article","created":{"date-parts":[[2022,3,25]],"date-time":"2022-03-25T15:31:21Z","timestamp":1648222281000},"page":"3521","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Therapeutic Potential of Combining IL-6 and TNF Blockade in a Mouse Model of Allergic Asthma"],"prefix":"10.3390","volume":"23","author":[{"given":"Olga A.","family":"Namakanova","sequence":"first","affiliation":[{"name":"Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia"},{"name":"Department of Immunology, Faculty of Biology, Lomonosov Moscow State University, 119234 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ekaterina A.","family":"Gorshkova","sequence":"additional","affiliation":[{"name":"Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia"},{"name":"Division of Immunobiology and Biomedicine, Center of Genetic and Life Sciences, Sirius University of Science and Technology, 354340 Federal Territory Sirius, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruslan V.","family":"Zvartsev","sequence":"additional","affiliation":[{"name":"Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergei A.","family":"Nedospasov","sequence":"additional","affiliation":[{"name":"Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia"},{"name":"Department of Immunology, Faculty of Biology, Lomonosov Moscow State University, 119234 Moscow, Russia"},{"name":"Division of Immunobiology and Biomedicine, Center of Genetic and Life Sciences, Sirius University of Science and Technology, 354340 Federal Territory Sirius, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina S.","family":"Drutskaya","sequence":"additional","affiliation":[{"name":"Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia"},{"name":"Division of Immunobiology and Biomedicine, Center of Genetic and Life Sciences, Sirius University of Science and Technology, 354340 Federal Territory Sirius, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ekaterina O.","family":"Gubernatorova","sequence":"additional","affiliation":[{"name":"Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia"},{"name":"Division of Immunobiology and Biomedicine, Center of Genetic and Life Sciences, Sirius University of Science and Technology, 354340 Federal Territory Sirius, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/s13223-018-0260-y","article-title":"Common allergies in urban adolescents and their relationships with asthma control and healthcare utilization","volume":"14","author":"Rhee","year":"2018","journal-title":"Allergy Asthma Clin. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1038\/nm.2731","article-title":"Innate and adaptive immune responses in asthma","volume":"18","author":"Holgate","year":"2012","journal-title":"Nat. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1016\/j.immuni.2019.03.018","article-title":"The Cytokines of Asthma","volume":"50","author":"Lambrecht","year":"2019","journal-title":"Immunity"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1094","DOI":"10.1164\/rccm.201405-0859PP","article-title":"IL-17 in severe asthma. Where do we stand?","volume":"190","author":"Chesne","year":"2014","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3181","DOI":"10.1182\/blood.V86.8.3181.3181","article-title":"Glucocorticoids inhibit apoptosis of human neutrophils","volume":"86","author":"Liles","year":"1995","journal-title":"Blood"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"556","DOI":"10.2174\/138945011794751555","article-title":"The molecular mechanisms of glucocorticoids-mediated neutrophil survival","volume":"12","author":"Saffar","year":"2011","journal-title":"Curr. Drug Targets"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2475","DOI":"10.1056\/NEJMoa1804093","article-title":"Efficacy and Safety of Dupilumab in Glucocorticoid-Dependent Severe Asthma","volume":"378","author":"Rabe","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1007\/s12325-018-0702-4","article-title":"Liberty Asthma QUEST: Phase 3 Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate Dupilumab Efficacy\/Safety in Patients with Uncontrolled, Moderate-to-Severe Asthma","volume":"35","author":"Busse","year":"2018","journal-title":"Adv. Ther."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2455","DOI":"10.1056\/NEJMoa1304048","article-title":"Dupilumab in persistent asthma with elevated eosinophil levels","volume":"368","author":"Wenzel","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2090","DOI":"10.1111\/all.14768","article-title":"Sputum TNF markers are increased in neutrophilic and severe asthma and are reduced by azithromycin treatment","volume":"76","author":"Niessen","year":"2021","journal-title":"Allergy"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"5411","DOI":"10.4049\/jimmunol.154.10.5411","article-title":"TNF-alpha mediates recruitment of neutrophils and eosinophils during airway inflammation","volume":"154","author":"Lukacs","year":"1995","journal-title":"J. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1111\/j.1365-2567.2006.02499.x","article-title":"TRAF1 regulates recruitment of lymphocytes and, to a lesser extent, neutrophils, myeloid dendritic cells and monocytes to the lung airways following lipopolysaccharide inhalation","volume":"120","author":"Oyoshi","year":"2007","journal-title":"Immunology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2085","DOI":"10.1002\/eji.1830181233","article-title":"Tumor necrosis factor alpha stimulates leukotriene production in vivo","volume":"18","author":"Huber","year":"1988","journal-title":"Eur. J. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1186\/rr12","article-title":"Activation of tumor necrosis factor receptor 1 in airway smooth muscle: A potential pathway that modulates bronchial hyper-responsiveness in asthma?","volume":"1","author":"Amrani","year":"2000","journal-title":"Respir. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.ajpath.2021.10.007","article-title":"Cellular Mechanism Underlying the Facilitation of Contractile Response Induced by Tumor Necrosis Factor-alpha in Mouse Tracheal Smooth Muscle","volume":"192","author":"Zhang","year":"2022","journal-title":"Am. J. Pathol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Lechner, A., Henkel, F.D.R., Hartung, F., Bohnacker, S., Alessandrini, F., Gubernatorova, E.O., Drutskaya, M.S., Angioni, C., Schreiber, Y., and Haimerl, P. (2021). Macrophages acquire a TNF-dependent inflammatory memory in allergic asthma. J. Allergy Clin. Immunol.","DOI":"10.1016\/j.jaci.2021.11.026"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1164\/rccm.200809-1512OC","article-title":"A randomized, double-blind, placebo-controlled study of tumor necrosis factor-alpha blockade in severe persistent asthma","volume":"179","author":"Wenzel","year":"2009","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.1056\/NEJMoa011110","article-title":"Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent","volume":"345","author":"Keane","year":"2001","journal-title":"N. Engl. J. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1740","DOI":"10.1002\/art.20311","article-title":"Lymphoma in rheumatoid arthritis: The effect of methotrexate and anti-tumor necrosis factor therapy in 18,572 patients","volume":"50","author":"Wolfe","year":"2004","journal-title":"Arthritis Rheum."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"155654","DOI":"10.1016\/j.cyto.2021.155654","article-title":"Role of IL-6 in the commitment of T cell subsets","volume":"146","author":"Korn","year":"2021","journal-title":"Cytokine"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/s13223-020-00504-3","article-title":"Relationship between Th17-mediated immunity and airway inflammation in childhood neutrophilic asthma","volume":"17","author":"Wei","year":"2021","journal-title":"Allergy Asthma Clin. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1016\/j.jaci.2021.12.769","article-title":"TH17 cells and corticosteroid insensitivity in severe asthma","volume":"149","author":"Xie","year":"2022","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/s13223-015-0081-1","article-title":"Therapeutic potential of anti-IL-6 therapies for granulocytic airway inflammation in asthma","volume":"11","author":"Chu","year":"2015","journal-title":"Allergy Asthma Clin. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"583042","DOI":"10.3389\/fimmu.2020.583042","article-title":"Cross-Talk Between Alveolar Macrophages and Lung Epithelial Cells is Essential to Maintain Lung Homeostasis","volume":"11","author":"Bissonnette","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1097\/ACI.0000000000000336","article-title":"IgE and eosinophils as therapeutic targets in asthma","volume":"17","author":"Patel","year":"2017","journal-title":"Curr. Opin. Allergy Clin. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1080\/17476348.2018.1505507","article-title":"The concepts of asthma endotypes and phenotypes to guide current and novel treatment strategies","volume":"12","author":"Ozdemir","year":"2018","journal-title":"Expert Rev. Respir. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1080\/02770903.2017.1283696","article-title":"Th-17 regulatory cytokines IL-21, IL-23, and IL-6 enhance neutrophil production of IL-17 cytokines during asthma","volume":"54","author":"Halwani","year":"2017","journal-title":"J. Asthma"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1016\/j.it.2017.07.003","article-title":"Neutrophilic Inflammation in Asthma and Association with Disease Severity","volume":"38","author":"Ray","year":"2017","journal-title":"Trends Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1111\/all.13619","article-title":"Tight junction, mucin, and inflammasome-related molecules are differentially expressed in eosinophilic, mixed, and neutrophilic experimental asthma in mice","volume":"74","author":"Tan","year":"2019","journal-title":"Allergy"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1165\/rcmb.2004-0288OC","article-title":"Tumor necrosis factor-alpha induces transforming growth factor-beta1 expression in lung fibroblasts through the extracellular signal-regulated kinase pathway","volume":"32","author":"Sullivan","year":"2005","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"155536","DOI":"10.1016\/j.cyto.2021.155536","article-title":"Interleukin-6 participates in human pancreatic stellate cell activation and collagen I production via TGF-beta1\/Smad pathway","volume":"143","author":"Zheng","year":"2021","journal-title":"Cytokine"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1055\/s-0037-1607391","article-title":"Diagnosis and Management of Severe Asthma","volume":"39","author":"Chung","year":"2018","journal-title":"Semin. Respir. Crit. Care Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"667","DOI":"10.2174\/138161211795429028","article-title":"Immunopathogenesis of severe asthma","volume":"17","author":"Brightling","year":"2011","journal-title":"Curr. Pharm. Des."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1183\/09031936.00202013","article-title":"International ERS\/ATS guidelines on definition, evaluation and treatment of severe asthma","volume":"43","author":"Chung","year":"2014","journal-title":"Eur. Respir. J."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"601842","DOI":"10.3389\/fimmu.2021.601842","article-title":"Novel Anti-Cytokine Strategies for Prevention and Treatment of Respiratory Allergic Diseases","volume":"12","author":"Gubernatorova","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1186\/s12931-019-1134-7","article-title":"Mepolizumab reduces exacerbations in patients with severe eosinophilic asthma, irrespective of body weight\/body mass index: Meta-analysis of MENSA and MUSCA","volume":"20","author":"Albers","year":"2019","journal-title":"Respir. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1016\/j.chest.2016.03.032","article-title":"Reslizumab for Inadequately Controlled Asthma With Elevated Blood Eosinophil Levels: A Randomized Phase 3 Study","volume":"150","author":"Bjermer","year":"2016","journal-title":"Chest"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.anai.2019.10.006","article-title":"Benralizumab efficacy for patients with fixed airflow obstruction and severe, uncontrolled eosinophilic asthma","volume":"124","author":"Chipps","year":"2020","journal-title":"Ann. Allergy Asthma Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1800","DOI":"10.1056\/NEJMoa2034975","article-title":"Tezepelumab in Adults and Adolescents with Severe, Uncontrolled Asthma","volume":"384","author":"Corren","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3313","DOI":"10.1172\/JCI90890","article-title":"TNF is required for TLR ligand-mediated but not protease-mediated allergic airway inflammation","volume":"127","author":"Whitehead","year":"2017","journal-title":"J. Clin. Invest."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1056\/NEJMoa050580","article-title":"Evidence of a role of tumor necrosis factor alpha in refractory asthma","volume":"354","author":"Berry","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"15025","DOI":"10.1038\/nrdp.2015.25","article-title":"Asthma","volume":"1","author":"Holgate","year":"2015","journal-title":"Nat. Rev. Dis. Primers."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1164\/rccm.200601-072OC","article-title":"The effects of a monoclonal antibody directed against tumor necrosis factor-alpha in asthma","volume":"174","author":"Erin","year":"2006","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"21","DOI":"10.2174\/1874306401307010021","article-title":"Monoclonal Anti-TNF-alpha Antibodies for Severe Steroid-Dependent Asthma: A Case Series","volume":"7","author":"Taille","year":"2013","journal-title":"Open Respir. Med. J."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1016\/1074-7613(95)90001-2","article-title":"Tumor necrosis factor-alpha is required in the protective immune response against Mycobacterium tuberculosis in mice","volume":"2","author":"Flynn","year":"1995","journal-title":"Immunity"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1111\/j.1440-1843.2008.01278.x","article-title":"Evaluation of the anti-inflammatory effect of infliximab in a mouse model of acute asthma","volume":"13","author":"Deveci","year":"2008","journal-title":"Respirology"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1111\/j.1365-2222.2005.02407.x","article-title":"Anti-tumor necrosis factor-alpha antibody treatment reduces pulmonary inflammation and methacholine hyper-responsiveness in a murine asthma model induced by house dust","volume":"36","author":"Kim","year":"2006","journal-title":"Clin. Exp. Allergy"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/S1081-1206(10)60528-5","article-title":"Decrease in airway mucous gene expression caused by treatment with anti-tumor necrosis factor alpha in a murine model of allergic asthma","volume":"103","author":"Busse","year":"2009","journal-title":"Ann. Allergy Asthma Immunol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.cytogfr.2020.05.009","article-title":"IL-6: Relevance for immunopathology of SARS-CoV-2","volume":"53","author":"Gubernatorova","year":"2020","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.clim.2008.08.018","article-title":"The effects of IL-6 on CD4 T cell responses","volume":"130","author":"Dienz","year":"2009","journal-title":"Clin. Immunol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2720","DOI":"10.4049\/jimmunol.174.5.2720","article-title":"IL-6 plays a unique role in initiating c-Maf expression during early stage of CD4 T cell activation","volume":"174","author":"Yang","year":"2005","journal-title":"J. Immunol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1016\/j.it.2009.09.009","article-title":"Suppressors of cytokine signaling (SOCS) in T cell differentiation, maturation, and function","volume":"30","author":"Palmer","year":"2009","journal-title":"Trends Immunol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1830","DOI":"10.1002\/eji.201040391","article-title":"IL-6: Regulator of Treg\/Th17 balance","volume":"40","author":"Kimura","year":"2010","journal-title":"Eur. J. Immunol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2718","DOI":"10.3389\/fimmu.2018.02718","article-title":"Non-redundant Functions of IL-6 Produced by Macrophages and Dendritic Cells in Allergic Airway Inflammation","volume":"9","author":"Gubernatorova","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1152\/ajplung.00288.2014","article-title":"IL-6 trans-signaling increases expression of airways disease genes in airway smooth muscle","volume":"309","author":"Robinson","year":"2015","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.1016\/j.jaip.2019.02.043","article-title":"Treatment of severe persistent asthma with IL-6 receptor blockade","volume":"7","author":"Esty","year":"2019","journal-title":"J. Allergy Clin. Immunol. Pract."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1002\/cti2.1044","article-title":"Effects of interleukin-6 receptor blockade on allergen-induced airway responses in mild asthmatics","volume":"8","author":"Revez","year":"2019","journal-title":"Clin. Transl. Immunol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1800948","DOI":"10.1183\/13993003.00948-2018","article-title":"Tralokinumab did not demonstrate oral corticosteroid-sparing effects in severe asthma","volume":"53","author":"Busse","year":"2019","journal-title":"Eur. Respir. J."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1016\/S2213-2600(16)30265-X","article-title":"Efficacy and safety of lebrikizumab in patients with uncontrolled asthma (LAVOLTA I and LAVOLTA II): Replicate, phase 3, randomised, double-blind, placebo-controlled trials","volume":"4","author":"Hanania","year":"2016","journal-title":"Lancet Respir. Med."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1016\/j.iac.2004.06.008","article-title":"Anti-interleukin-4 therapy","volume":"24","author":"Steinke","year":"2004","journal-title":"Immunol. Allergy Clin. N. Am."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1586\/1744666X.4.6.743","article-title":"Use of biologicals as immunotherapy in asthma and related diseases","volume":"4","author":"Walker","year":"2008","journal-title":"Expert Rev. Clin. Immunol."},{"key":"ref_62","first-page":"269","article-title":"Role of IL-6 and TNF in thermoregulation and survival during sepsis in mice","volume":"275","author":"Leon","year":"1998","journal-title":"Am. J. Physiol."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Kern, L., Mittenbuhler, M.J., Vesting, A.J., Ostermann, A.L., Wunderlich, C.M., and Wunderlich, F.T. (2018). Obesity-Induced TNFalpha and IL-6 Signaling: The Missing Link between Obesity and Inflammation-Driven Liver and Colorectal Cancers. Cancers Basel, 11.","DOI":"10.3390\/cancers11010024"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1186\/s13075-020-02229-5","article-title":"Interleukin-6 receptor blockade or TNFalpha inhibition for reducing glycaemia in patients with RA and diabetes: Post hoc analyses of three randomised, controlled trials","volume":"22","author":"Genovese","year":"2020","journal-title":"Arthritis Res. Ther."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"10472","DOI":"10.1038\/s41598-021-89925-7","article-title":"Integrated metabolomic analysis and cytokine profiling define clusters of immuno-metabolic correlation in new-onset psoriasis","volume":"11","author":"Tarentini","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1681\/ASN.2008070778","article-title":"IL-6 and TNF-alpha synergistically inhibit allograft acceptance","volume":"20","author":"Shen","year":"2009","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_67","first-page":"149","article-title":"Synergism of TNF-alpha and IFN-gamma triggers inflammatory cell death, tissue damage, and mortality in SARS-CoV-2 infection and cytokine shock syndromes","volume":"184","author":"Karki","year":"2020","journal-title":"BioRxiv"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1016\/S0893-133X(99)00166-9","article-title":"Synergistic effects of interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha: Central monoamine, corticosterone, and behavioral variations","volume":"22","author":"Brebner","year":"2000","journal-title":"Neuropsychopharmacology"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1016\/j.immuni.2013.08.009","article-title":"Synergistic activation of inflammatory cytokine genes by interferon-gamma-induced chromatin remodeling and toll-like receptor signaling","volume":"39","author":"Qiao","year":"2013","journal-title":"Immunity"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1038\/nri2870","article-title":"Functions of T cells in asthma: More than just T(H)2 cells","volume":"10","author":"Lloyd","year":"2010","journal-title":"Nat. Rev. Immunol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1111\/j.1398-9995.2011.02576.x","article-title":"Th17 cells: New players in asthma pathogenesis","volume":"66","author":"Cosmi","year":"2011","journal-title":"Allergy"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"301ra129","DOI":"10.1126\/scitranslmed.aab3142","article-title":"TH2 and TH17 inflammatory pathways are reciprocally regulated in asthma","volume":"7","author":"Choy","year":"2015","journal-title":"Sci. Transl. Med."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"717962","DOI":"10.3389\/fmolb.2021.717962","article-title":"STAT3 and IL-6 Contribute to Corticosteroid Resistance in an OVA and Ozone-induced Asthma Model with Neutrophil Infiltration","volume":"8","author":"Xue","year":"2021","journal-title":"Front. Mol. Biosci."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Ritter, K., Sodenkamp, J.C., Holscher, A., Behrends, J., and Holscher, C. (2020). IL-6 is not Absolutely Essential for the Development of a TH17 Immune Response after an Aerosol Infection with Mycobacterium Tuberculosis H37rv. Cells, 10.","DOI":"10.3390\/cells10010009"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.alit.2021.07.004","article-title":"Prevention of IL-6 signaling ameliorates toluene diisocyanate-induced steroid-resistant asthma","volume":"71","author":"Chen","year":"2022","journal-title":"Allergol. Int."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1016\/j.jaci.2017.11.024","article-title":"TNF-alpha-induced protein 3 (TNFAIP3)\/A20 acts as a master switch in TNF-alpha blockade-driven IL-17A expression","volume":"142","author":"Urbano","year":"2018","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"191","DOI":"10.3389\/fmed.2020.00191","article-title":"Airway Remodeling in Asthma","volume":"7","author":"Hough","year":"2020","journal-title":"Front. Med. Lausanne"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1016\/j.jaci.2007.06.031","article-title":"Asthma therapy and airway remodeling","volume":"120","author":"Mauad","year":"2007","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1016\/j.jaci.2008.01.031","article-title":"Immunologic and inflammatory mechanisms that drive asthma progression to remodeling","volume":"121","author":"Broide","year":"2008","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1165\/rcmb.2010-0027TR","article-title":"Role of transforming growth factor-beta in airway remodeling in asthma","volume":"44","author":"Halwani","year":"2011","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1016\/j.coi.2007.07.017","article-title":"Cytokines and growth factors in airway remodeling in asthma","volume":"19","author":"Doherty","year":"2007","journal-title":"Curr. Opin. Immunol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1016\/j.jaci.2014.04.007","article-title":"Asthmatic airway epithelial cells differentially regulate fibroblast expression of extracellular matrix components","volume":"134","author":"Reeves","year":"2014","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1513\/pats.200907-067DP","article-title":"The role of the epithelium in airway remodeling in asthma","volume":"6","author":"Davies","year":"2009","journal-title":"Proc. Am. Thorac. Soc."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1152\/ajplung.00230.2006","article-title":"Effect of IL-6 trans-signaling on the pro-remodeling phenotype of airway smooth muscle","volume":"292","author":"Ammit","year":"2007","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"5774","DOI":"10.4049\/jimmunol.174.9.5774","article-title":"Manipulation of allergen-induced airway remodeling by treatment with anti-TGF-beta antibody: Effect on the Smad signaling pathway","volume":"174","author":"McMillan","year":"2005","journal-title":"J. Immunol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"e20190103","DOI":"10.1084\/jem.20190103","article-title":"Transforming growth factor-beta in tissue fibrosis","volume":"217","author":"Frangogiannis","year":"2020","journal-title":"J. Exp. Med."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1186\/s12931-020-1319-0","article-title":"TGF-beta pathway activation by idiopathic pulmonary fibrosis (IPF) fibroblast derived soluble factors is mediated by IL-6 trans-signaling","volume":"21","author":"Brook","year":"2020","journal-title":"Respir. Res."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1067\/mai.2003.1557","article-title":"Airway remodeling-associated mediators in moderate to severe asthma: Effect of steroids on TGF-beta, IL-11, IL-17, and type I and type III collagen expression","volume":"111","author":"Chakir","year":"2003","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1038\/nrd3003","article-title":"The safety and side effects of monoclonal antibodies","volume":"9","author":"Hansel","year":"2010","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"3006","DOI":"10.1073\/pnas.1520175113","article-title":"Cell-type-restricted anti-cytokine therapy: TNF inhibition from one pathogenic source","volume":"113","author":"Efimov","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1016\/j.arcmed.2019.10.002","article-title":"Aerosol Inhalation-mediated Delivery of an Adeno-associated Virus 5-expressed Antagonistic Interleukin-4 Mutant Ameliorates Experimental Murine Asthma","volume":"50","author":"Tian","year":"2019","journal-title":"Arch. Med. Res."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1242\/dmm.000323","article-title":"Mouse models of allergic asthma: Acute and chronic allergen challenge","volume":"1","author":"Nials","year":"2008","journal-title":"Dis. Model. Mech."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1007\/s00011-009-0054-2","article-title":"Mouse models of asthma: A comparison between C57BL\/6 and BALB\/c strains regarding bronchial responsiveness, inflammation, and cytokine production","volume":"58","author":"Gueders","year":"2009","journal-title":"Inflamm. Res."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1007\/978-1-4939-6786-5_10","article-title":"Murine Models of Allergic Asthma","volume":"1559","author":"Haspeslagh","year":"2017","journal-title":"Methods Mol. Biol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"537","DOI":"10.4168\/aair.2020.12.3.537","article-title":"An Alternative Dendritic Cell-Induced Murine Model of Asthma Exhibiting a Robust Th2\/Th17-Skewed Response","volume":"12","author":"Park","year":"2020","journal-title":"Allergy Asthma Immunol. Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/7\/3521\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:42:09Z","timestamp":1760136129000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/7\/3521"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,24]]},"references-count":95,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2022,4]]}},"alternative-id":["ijms23073521"],"URL":"https:\/\/doi.org\/10.3390\/ijms23073521","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,24]]}}}