Suppression of Autoimmune Arthritis by Small Molecule Inhibitors of the JAKSTAT Pathway 英文参考文献.docVIP

Pharmaceuticals 2010, 3, 1446-1455; doi:10.3390/ph3051446 OPEN ACCESS pharmaceuticals ISSN 1424-8247 /journal/pharmaceuticals Review Suppression of Autoimmune Arthritis by Small Molecule Inhibitors of the JAK/STAT Pathway Charles J. Malemud Division of Rheumatic Diseases, Departments of Medicine Anatomy, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, USA; E-Mail: cjm4@; Tel: +1-216-844-7846; Fax: +1-216-844-2288 Received: 26 March 2010; in revised form: 20 April 2010 / Accepted: 11 May 2010 / Published: 12 May 2010 Abstract: A skewed ratio of pro-inflammatory to anti-inflammatory cytokines, elevated growth factor synthesis and T- and B-lymphocyte activation are 3 hallmarks of rheumatoid arthritis (RA) pathology. Interleukin-6 (IL-6), IL-7, IL-17, IL-12/IL-23 and growth factors, granulocyte macrophage-colony stimulating factor, IL-3, and erythropoietin activate the Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) pathway. Evidence showed that STAT protein phosphorylation (p-STAT) by activated JAKs is permissive for p-STAT to act as transcription factors by binding to STAT-responsive gene promoter sequences. This event is critical for perpetuating RA, in part, by up-regulating pro-inflammatory cytokine gene transcription. Activation of JAK/STAT by cytokines and growth factors can induce ‘cross-talk’ with other signaling pathways by which Stress- Activated Protein/Mitogen-Activated Protein Kinase (SAP/MAPK) and Phosphatidylinositide-3-Kinase (PI3K)-mediated signaling are also activated. JAK-specific small molecule inhibitors (SMIs) were developed to test whether JAK/STAT pathway blockade would regulate autoimmune-mediated inflammation. JAK-specific SMI blockade inhibited p-STAT induced by pro-inflammatory cytokines in vitro. Systemically administered JAK-specific SMI blockade also ameliorated biomarkers of inflammation in well-validat