Targeting JAK/STAT Signaling Pathway in Inflammatory Diseases

Abstract

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-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-, 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.

Apoptosis Resistance in Rheumatoid Arthritis Synovial Tissue

“…However, activation (i.e. phosphorylation) of STAT1/STAT3/STAT6 was shown to precede the IFN-γ-mediated apoptotic response [43] suggesting that phosphoryation of JAKs was a mechanism likely to be responsible for TRAIL/DR5-induced apoptosis in FLS sensitized by IFN-γ. It should be obvious from the preceding section that although TRAIL/ DR5 appears to play an important role in the suppression of synovial tissue apoptosis in experimental arthritis, the real significance of TRAIL in human RA lies in demonstrating that TRAIL levels are elevated in human RA, and furthermore, that neutralization of TRAIL induces apoptosis.…”

“…Another mechanism that may explain the resistance of RASF to Fasinduced apoptosis involves the small-ubiquitin-like modifier (SUMO-1) protein [43]. SUMO-1 levels were shown to be increased in RASF [91].…”

Gene Therapy Outcomes in Experimental Models of Inflammatory Arthritis

“…DMARBDs were first discovered to be effective by altering intracellular signaling pathways and those gene expressional events t h a t h a v e p r o v e n t o b e r e l e v a n t t o R A pathogenesis and progression through the use of experimental studies in pre-clinical in vitro testing systems (Malemud, 2010;Malemud & Miller, 2008, Malemud & Pearlman, 2009Marone et al, 2008;Walker et al, 2006). Those DMARBDs that appeared to have significant modifying effects on immune deregulation were then shown to ameliorate arthritis by virtue of their capacity to delay the onset or reducing the severity of inflammatory arthritis in several well-validated small animal models of RA (Feely et al, 2009).…”

Recent advances in neutralizing the IL-6 pathway in arthritis

“…1 Several reviews of the published literature which focused on the relevant signal transduction pathways induced by IL-6 that lead to changes in immunologic status and in the progression of inflammatory responses in these disorders all appeared in 2006. [2][3][4][5][6][7][8][9] At that time, these summaries of the relevant in vitro and ex vivo studies mainly attempted to correlate IL-6 levels with disease activity in experimentally-induced animal models of human rheumatoid arthritis (RA).…”

“…A critical evaluation of the results of experimental and clinical studies will be provided and evidence presented as to why blockade of IL-6-mediated trans-signaling can be employed to suppress immune dysfunction and inflammation in arthritis. 1,[14][15][16] The results of the most recent studies have also helped define and identify additional novel targets where interventions originally focused on the IL-6/IL-6R/gp130 pathway may impact on the development and progression of arthritis and related rheumatic disorders. [17][18][19][20][21][22][23][24][25][26] …”