{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T00:16:17Z","timestamp":1793146577627,"version":"4.5.0"},"reference-count":79,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2011,4,1]],"date-time":"2011-04-01T00:00:00Z","timestamp":1301616000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2011,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Inhibitors of the JAK family of nonreceptor tyrosine kinases have demonstrated clinical efficacy in rheumatoid arthritis and other inflammatory disorders; however, the precise mechanisms by which JAK inhibition improves inflammatory immune responses remain unclear. In this study, we examined the mode of action of tofacitinib (CP-690,550) on JAK\/STAT signaling pathways involved in adaptive and innate immune responses. To determine the extent of inhibition of specific JAK\/STAT-dependent pathways, we analyzed cytokine stimulation of mouse and human T cells in vitro. We also investigated the consequences of CP-690,550 treatment on Th cell differentiation of naive murine CD4+ T cells. CP-690,550 inhibited IL-4\u2013dependent Th2 cell differentiation and interestingly also interfered with Th17 cell differentiation. Expression of IL-23 receptor and the Th17 cytokines IL-17A, IL-17F, and IL-22 were blocked when naive Th cells were stimulated with IL-6 and IL-23. In contrast, IL-17A production was enhanced when Th17 cells were differentiated in the presence of TGF-\u03b2. Moreover, CP-690,550 also prevented the activation of STAT1, induction of T-bet, and subsequent generation of Th1 cells. In a model of established arthritis, CP-690,550 rapidly improved disease by inhibiting the production of inflammatory mediators and suppressing STAT1-dependent genes in joint tissue. Furthermore, efficacy in this disease model correlated with the inhibition of both JAK1 and JAK3 signaling pathways. CP-690,550 also modulated innate responses to LPS in vivo through a mechanism likely involving the inhibition of STAT1 signaling. Thus, CP-690,550 may improve autoimmune diseases and prevent transplant rejection by suppressing the differentiation of pathogenic Th1 and Th17 cells as well as innate immune cell signaling.<\/jats:p>","DOI":"10.4049\/jimmunol.1003668","type":"journal-article","created":{"date-parts":[[2011,3,8]],"date-time":"2011-03-08T12:54:42Z","timestamp":1299588882000},"page":"4234-4243","source":"Crossref","is-referenced-by-count":588,"title":["Modulation of Innate and Adaptive Immune Responses by Tofacitinib (CP-690,550)"],"prefix":"10.1093","volume":"186","author":[{"given":"Kamran","family":"Ghoreschi","sequence":"first","affiliation":[{"name":"Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health , Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael I","family":"Jesson","sequence":"additional","affiliation":[{"name":"St. Louis Laboratories, Pfizer Global Research and Development , Chesterfield, MO 63017"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiong","family":"Li","sequence":"additional","affiliation":[{"name":"St. Louis Laboratories, Pfizer Global Research and Development , Chesterfield, MO 63017"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamie L","family":"Lee","sequence":"additional","affiliation":[{"name":"St. Louis Laboratories, Pfizer Global Research and Development , Chesterfield, MO 63017"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarbani","family":"Ghosh","sequence":"additional","affiliation":[{"name":"St. Louis Laboratories, Pfizer Global Research and Development , Chesterfield, MO 63017"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason W","family":"Alsup","sequence":"additional","affiliation":[{"name":"St. Louis Laboratories, Pfizer Global Research and Development , Chesterfield, MO 63017"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James D","family":"Warner","sequence":"additional","affiliation":[{"name":"St. Louis Laboratories, Pfizer Global Research and Development , Chesterfield, MO 63017"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masao","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Translational Immunology Section, Office of Science and Technology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health , Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott M","family":"Steward-Tharp","sequence":"additional","affiliation":[{"name":"Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health , Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Gadina","sequence":"additional","affiliation":[{"name":"Translational Immunology Section, Office of Science and Technology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health , Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig J","family":"Thomas","sequence":"additional","affiliation":[{"name":"National Institutes of Health Chemical Genomics Center, National Human Genome Research Institute, National Institutes of Health , Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John C","family":"Minnerly","sequence":"additional","affiliation":[{"name":"St. Louis Laboratories, Pfizer Global Research and Development , Chesterfield, MO 63017"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chad E","family":"Storer","sequence":"additional","affiliation":[{"name":"St. Louis Laboratories, Pfizer Global Research and Development , Chesterfield, MO 63017"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy P","family":"LaBranche","sequence":"additional","affiliation":[{"name":"St. Louis Laboratories, Pfizer Global Research and Development , Chesterfield, MO 63017"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zaher A","family":"Radi","sequence":"additional","affiliation":[{"name":"St. Louis Laboratories, Pfizer Global Research and Development , Chesterfield, MO 63017"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin E","family":"Dowty","sequence":"additional","affiliation":[{"name":"St. Louis Laboratories, Pfizer Global Research and Development , Chesterfield, MO 63017"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard D","family":"Head","sequence":"additional","affiliation":[{"name":"St. Louis Laboratories, Pfizer Global Research and Development , Chesterfield, MO 63017"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debra M","family":"Meyer","sequence":"additional","affiliation":[{"name":"St. Louis Laboratories, Pfizer Global Research and Development , Chesterfield, MO 63017"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nandini","family":"Kishore","sequence":"additional","affiliation":[{"name":"St. Louis Laboratories, Pfizer Global Research and Development , Chesterfield, MO 63017"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John J","family":"O\u2019Shea","sequence":"additional","affiliation":[{"name":"Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health , Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2011,4,1]]},"reference":[{"key":"2025032411191468200_r1","doi-asserted-by":"crossref","first-page":"6724","DOI":"10.1038\/sj.onc.1210757","article-title":"Hematopoietic cytokine receptor signaling","volume":"26","author":"Baker","year":"2007","journal-title":"Oncogene"},{"key":"2025032411191468200_r2","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1111\/j.1600-065X.2008.00754.x","article-title":"Janus kinases in immune cell signaling","volume":"228","author":"Ghoreschi","year":"2009","journal-title":"Immunol. 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