Targeting JAK/STAT Signaling Pathway in Inflammatory Diseases

In immune-mediated chronic inflammation the balance between pro-inflammatory and anti-inflammatory cytokines is skewed so that elevated levels of circulating pro-inflammatory cytokines of the interleukin (IL), interferon (IFN) protein families and TNF-alpha is favored. Several of the pro-inflammatory IL-family cytokines, including most prominently, IL-6, IL-12, IL-17, IL-23, as well as IFN-gamma, activate the Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) signaling pathway where phosphorylated (i.e. activated) STAT proteins become potent transcription factors for specific STAT-target genes. Moreover, 'cross-talk' between JAK/STAT signaling, SAP/MAPK and the phosphatidyl inositide-3-kinase (PI3K) pathway has been demonstrated. Thus, activation of the SAP/MAPK and PI3K pathways by JAK/STAT can initiate pleiotypic cellular responses that regulate cellular proliferation, survival, development and apoptosis. Further, inflammatory responses typically seen in rheumatoid arthritis, irritable bowel disease, chronic heart failure and diseases of the eye appear to accelerate when the JAK/STAT pathway itself becomes dysregulated. Of note, the outcomes of several human clinical trials demonstrated efficacy in reducing some objective markers of chronic inflammation by inhibiting IL-6-mediated signaling. In addition, evidence from one of these trials showed that suppression of IL-6 signaling also dampened STAT phosphorylation. This result suggested that the targeting of JAK/STAT signaling with small molecule inhibitors may also suppress chronic inflammatory responses.