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

被引：188

作者：

Zanin-Zhorov, Alexandra ^{[1
]}

Weiss, Jonathan M. ^{[1
]}

Nyuydzefe, Melanie S. ^{[1
]}

Chen, Wei ^{[1
]}

Scher, Jose U. ^{[2
]}

Mo, Rigen ^{[1
]}

Depoil, David ^{[5
]}

Rao, Nishta ^{[1
]}

Liu, Ben ^{[3
]}

Wei, Jianlu ^{[3
,4
]}

Lucas, Sarah ^{[1
]}

Koslow, Matthew ^{[1
]}

Roche, Maria ^{[1
]}

Schueller, Olivier ^{[6
]}

Weiss, Sara ^{[1
]}

Poyurovsky, Masha V. ^{[1
]}

Tonra, James ^{[1
]}

Hippen, Keli L. ^{[7
]}

Dustin, Michael L. ^{[5
]}

Blazar, Bruce R. ^{[7
]}

Liu, Chuan-ju ^{[3
]}

Waksal, Samuel D. ^{[1
]}

机构：

[1] Kadmon Res Inst, New York, NY 10016 USA

[2] NYU, Sch Med, Div Rheumatol, New York, NY 10003 USA

[3] NYU, Sch Med, Dept Orthopaed Surg, New York, NY 10003 USA

[4] New York Univ Hosp Joint Dis, New York, NY 10003 USA

[5] NYU, Skirball Inst Biomol Med, Mol Pathogenesis Program, Dept Pathol,Sch Med, New York, NY 10016 USA

[6] Nano Terra Life Sci, Brighton, MA 02135 USA

[7] Univ Minnesota, Ctr Canc, Dept Pediat, Div Blood & Marrow Transplantat, Minneapolis, MN 55455 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2014年 / 111卷 / 47期

关键词：

Human T cells; autoimmunity; proinflammatory cytokines; STAT3; STAT5; GROWTH-FACTOR-BETA; RHEUMATOID-ARTHRITIS; RHO-KINASE; TRANSCRIPTIONAL REGULATION; TH17; CELLS; DIFFERENTIATION; ACTIVATION; STAT3; PHOSPHORYLATION; AUTOIMMUNITY;

D O I：

10.1073/pnas.1414189111

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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-gamma 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 gamma t 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.

引用

页码：16814 / 16819

页数：6

共 41 条

[1] Simultaneous tyrosine and serine phosphorylation of STAT3 transcription factor is involved in Rho A GTPase oncogenic transformation [J].