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Proc Natl Acad Sci U S A. 2014 Nov 25;111(47):16814-9. doi: 10.1073/pnas.1414189111. Epub 2014 Nov 10.

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

Author information

1
Kadmon Research Institute, New York, NY 10016; alexandra.zanin-zhorov@kadmon.com.
2
Kadmon Research Institute, New York, NY 10016;
3
Division of Rheumatology and.
4
Molecular Pathogenesis Program, Skirball Institute of Biomolecular Medicine, Department of Pathology, New York University School of Medicine, New York, NY 10016;
5
Department of Orthopaedic Surgery, New York University School of Medicine and New York University Hospital for Joint Diseases, New York, NY 10003;
6
Nano Terra Life Sciences, Brighton, MA 02135; and.
7
Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota Cancer Center, Minneapolis, MN 55455.

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.

KEYWORDS:

Human T cells; STAT3; STAT5; autoimmunity; proinflammatory cytokines

PMID:
25385601
PMCID:
PMC4250132
DOI:
10.1073/pnas.1414189111
[Indexed for MEDLINE]
Free PMC Article

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