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Selective oral ROCK2 inhibitor down-regulates IL-21 and IL-17 secretion in human T cells via STAT3-dependent mechanism

Author:
Zanin-Zhorov, Alexandra, Weiss, Jonathan M., Nyuydzefe, Melanie S., Chen, Wei, Scher, Jose U., Mo, Rigen, Depoil, David, Rao, Nishta, Liu, Ben, Wei, Jianlu, Lucas, Sarah, Koslow, Matthew, Roche, Maria, Schueller, Olivier, Weiss, Sara, Poyurovsky, Masha V., Tonra, James, Hippen, Keli L., Dustin, Michael L., Blazar, Bruce R., Liu, Chuan-ju, Waksal, Samuel D.
Source:
Proceedings of the National Academy of Sciences of the United States of America 2014 v.111 no.47 pp. 16814-16819
ISSN:
0027-8424
Subject:
T-lymphocytes, autoimmunity, humans, immune response, inflammation, interleukin-17, interleukin-21, mice, phosphorylation, secretion, signal transduction
Abstract:
Rho-associated kinase 2 (ROCK2) regulates the secretion of proinflammatory cytokines and the development of autoimmunity in mice. Data from a phase 1 clinical trial demonstrate that oral administration of KD025, a selective ROCK2 inhibitor, to healthy human subjects down-regulates the ability of T cells to secrete IL-21 and IL-17 by 90% and 60%, respectively, but not IFN-γ in response to T-cell receptor stimulation in vitro. Pharmacological inhibition with KD025 or siRNA-mediated inhibition of ROCK2, but not ROCK1, significantly diminished STAT3 phosphorylation and binding to IL-17 and IL-21 promoters and reduced IFN regulatory factor 4 and nuclear hormone RAR-related orphan receptor γt protein levels in T cells derived from healthy subjects or rheumatoid arthritis patients. Simultaneously, treatment with KD025 also promotes the suppressive function of regulatory T cells through up-regulation of STAT5 phosphorylation and positive regulation of forkhead box p3 expression. The administration of KD025 in vivo down-regulates the progression of collagen-induced arthritis in mice via targeting of the Th17-mediated pathway. Thus, ROCK2 signaling appears to be instrumental in regulating the balance between proinflammatory and regulatory T-cell subsets. Targeting of ROCK2 in man may therefore restore disrupted immune homeostasis and have a role in the treatment of autoimmunity.
Agid:
1787912