Differential activation of JAK enzymes in rheumatoid arthritis and autoimmune disorders by pro-inflammatory cytokines: potential drug targets

Abstract:

Although several pro-inflammatory cytokines including interleukin-6 (IL-6), IL-7, IL-12/IL-23, IL-17, IL-2, interferon, and the anti-inflammatory cytokines, IL-4/IL-13, IL-10, and IL-22, all activate the Janus kinase/signal transducers and activators of transcription (JAK/ STAT) pathway, in autoimmune disorders, a skewing of the cytokine repertoire in favor of pro-inflammatory cytokines results in amplifying the effects of pro-inflammatory cytokines. An apparent deficiency of anti-inflammatory cytokines to counterbalance the ‘ramping up’ of pro-inflammatory cytokine-mediated activation of JAK/STAT is also significant, while endogenous negative regulators of cytokine signaling and JAK/STAT activation may also be compromised. In addition, JAK/STAT pathway activation can result in activation of stress-activated protein/mitogen-activated protein kinase (SAP/MAPK) and phosphatidylinositol-3-kinase/ Akt/mammalian target of rapamycin pathways that are instrumental in promoting matrix metalloproteinase gene expression, aberrant cell survival, and osteoclast differentiation. The critical role played by pro-inflammatory cytokines in differentially activating JAK/STAT and parallel signal transduction pathways resulted in the development of several cytokine/cytokine receptor neutralizing monoclonal antibodies and fusion proteins that are currently employed for treating rheumatoid arthritis, Crohn’s disease, and psoriasis. Small molecule inhibitors (SMIs) that target specific JAK enzymes have led to the development of CP690550, a JAK3-specific SMI, which is the first JAK-specific SMI to reach phase III in a rheumatoid arthritis clinical trial.

Keywords::

• autoimmunity
• cytokines
• inflammation
• Janus kinase
• signal transducers and activators of transcription
• small molecule inhibitors