Pharmaceuticals 2010, 3(5), 1446-1455; doi:10.3390/ph3051446
Review

Suppression of Autoimmune Arthritis by Small Molecule Inhibitors of the JAK/STAT Pathway

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Received: 26 March 2010; in revised form: 20 April 2010 / Accepted: 11 May 2010 / Published: 12 May 2010
(This article belongs to the Special Issue Protein Kinase Inhibitors)
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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-validated arthritis animal models. A few JAK-specific SMIs have made their way into RA clinical trials. In fact, the JAK3-specific SMI, CP-690,500 is the first JAK/STAT SMI to be assessed for clinical efficacy in a Phase III RA trial.
Keywords: arthritis; autoimmune; Janus kinase; signal transducers and activators of transcription; small molecule inhibitor
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MDPI and ACS Style

Malemud, C.J. Suppression of Autoimmune Arthritis by Small Molecule Inhibitors of the JAK/STAT Pathway. Pharmaceuticals 2010, 3, 1446-1455.

AMA Style

Malemud CJ. Suppression of Autoimmune Arthritis by Small Molecule Inhibitors of the JAK/STAT Pathway. Pharmaceuticals. 2010; 3(5):1446-1455.

Chicago/Turabian Style

Malemud, Charles J. 2010. "Suppression of Autoimmune Arthritis by Small Molecule Inhibitors of the JAK/STAT Pathway." Pharmaceuticals 3, no. 5: 1446-1455.

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