Modulation of innate and adaptive immune responses by tofacitinib (CP-690,550)

Kamran Ghoreschi, Michael I. Jesson, Xiong Li, Jamie L. Lee, Sarbani Ghosh, Jason W. Alsup, James D. Warner, Masao Tanaka, Scott M. Steward-Tharp, Massimo Gadina, Craig J. Thomas, John C. Minnerly, Chad E. Storer, Timothy P. LaBranche, Zaher A. Radi, Martin E. Dowty, Richard D. Head, Debra M. Meyer, Nandini Kishore, John J. O'Shea

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364 Scopus citations

Abstract

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-dependent 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-b. 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.

Original languageEnglish
Pages (from-to)4234-4243
Number of pages10
JournalJournal of Immunology
Volume186
Issue number7
DOIs
StatePublished - Apr 1 2011
Externally publishedYes

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    Ghoreschi, K., Jesson, M. I., Li, X., Lee, J. L., Ghosh, S., Alsup, J. W., Warner, J. D., Tanaka, M., Steward-Tharp, S. M., Gadina, M., Thomas, C. J., Minnerly, J. C., Storer, C. E., LaBranche, T. P., Radi, Z. A., Dowty, M. E., Head, R. D., Meyer, D. M., Kishore, N., & O'Shea, J. J. (2011). Modulation of innate and adaptive immune responses by tofacitinib (CP-690,550). Journal of Immunology, 186(7), 4234-4243. https://doi.org/10.4049/jimmunol.1003668