Selective oral ROCK2 inhibitor down-regulates IL-21 and IL-17 secretion in human T cells via STAT3-dependent mechanism.
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.
Kadmon Research Institute, New York, NY 10016; alexandra.zanin-zhorov@kadmon.com.
Alexandra
A
Zanin-Zhorov
Kadmon Research Institute, New York, NY 10016;
Jonathan M
JM
Weiss
Kadmon Research Institute, New York, NY 10016;
Melanie S
MS
Nyuydzefe
Kadmon Research Institute, New York, NY 10016;
Wei
W
Chen
Division of Rheumatology and.
Jose U
JU
Scher
Kadmon Research Institute, New York, NY 10016;
Rigen
R
Mo
Molecular Pathogenesis Program, Skirball Institute of Biomolecular Medicine, Department of Pathology, New York University School of Medicine, New York, NY 10016;
David
D
Depoil
Kadmon Research Institute, New York, NY 10016;
Nishta
N
Rao
Department of Orthopaedic Surgery, New York University School of Medicine and New York University Hospital for Joint Diseases, New York, NY 10003;
Ben
B
Liu
Department of Orthopaedic Surgery, New York University School of Medicine and New York University Hospital for Joint Diseases, New York, NY 10003;
Jianlu
J
Wei
Kadmon Research Institute, New York, NY 10016;
Sarah
S
Lucas
Kadmon Research Institute, New York, NY 10016;
Matthew
M
Koslow
Kadmon Research Institute, New York, NY 10016;
Maria
M
Roche
Nano Terra Life Sciences, Brighton, MA 02135; and.
Olivier
O
Schueller
Kadmon Research Institute, New York, NY 10016;
Sara
S
Weiss
Kadmon Research Institute, New York, NY 10016;
Masha V
MV
Poyurovsky
Kadmon Research Institute, New York, NY 10016;
James
J
Tonra
Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota Cancer Center, Minneapolis, MN 55455.
Keli L
KL
Hippen
Molecular Pathogenesis Program, Skirball Institute of Biomolecular Medicine, Department of Pathology, New York University School of Medicine, New York, NY 10016;
Michael L
ML
Dustin
Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota Cancer Center, Minneapolis, MN 55455.
Bruce R
BR
Blazar
Department of Orthopaedic Surgery, New York University School of Medicine and New York University Hospital for Joint Diseases, New York, NY 10003;
Chuan-ju
CJ
Liu
Kadmon Research Institute, New York, NY 10016;
Samuel D
SD
Waksal
D000284:Administration, Oral; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism*; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*; D000098546:Interleukin-21
D020381:Interleukin-17; D007378:Interleukins; D047428:Protein Kinase Inhibitors; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C515852:ROCK2 protein, human; D054460:rho-Associated Kinases; D000098546:Interleukin-21
Human T cells; STAT3; STAT5; autoimmunity; proinflammatory cytokines