Modulation of Innate and Adaptive Immune Responses by Tofacitinib (CP-690,550)
By K. Ghoreschi, M. Jesson, Xiong Li, Jamie Lee, Sarbani Ghosh, Jason W Alsup, James D Warner, Masao Tanaka, Scott M. Steward-Tharp, M. Gadina and 10 more. Journal of Immunology, 2011
636 citations recorded by the source corpus.
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-β. 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.
Subfields: Genetics, Immunology, Oncology
View Paper: https://www.semanticscholar.org/paper/0ab040479d691e52cd54b8be7ea6f48b419257a5
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Citations in the corpus
- Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis. (2012, neutral): “Smoker 2/48 (4) 3/31 (10) 4/33 (12) 1/32 (3) 4/49 (8)”
- JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age (2015, background): “A number of inhibitors that target different JAKs have been approved or are in phase I–III studies for treating myelofibrosis (23, 32– 34), acute myeloid leukemia (23), lymphoma (23), and rheumatoid arthritis (23, 35, 36).”
- The role of JAK-STAT signaling pathway and its regulators in the fate of T helper cells (2017, background): “Although only few JAK inhibitors (JAKinib) are FDA approved, other JAKinibs and possible STAT inhibitors are being developed by passing preclinical evaluations and clinical trials [118].”
- The JAK/STAT signaling pathway: from bench to clinic (2021, background): “Nevertheless, tofacitinib increased serum levels of IL-35 and IL-35 might be an indicator of the disease activity attenuated by tofacitinib efficacy.(350,351) Tofacitinib is effective in preclinical studies and has been applied in various phase 2 and phase 3 clinical trials.”