The role of the JAK/STAT signal pathway in rheumatoid arthritis

Abstract

Proinflammatory cytokine activation of the Janus kinase/signal transducers and activators of transcription (JAK/STAT) signal transduction pathway is a critical event in the pathogenesis and progression of rheumatoid arthritis. Under normal conditions, JAK/STAT signaling reflects the influence of negative regulators of JAK/STAT, exemplified by the suppressor of cytokine signaling and protein inhibitor of activated STAT. However, in rheumatoid arthritis (RA) both of these regulators are dysfunctional. Thus, continuous activation of JAK/STAT signaling in RA synovial joints results in the elevated level of matrix metalloproteinase gene expression, increased frequency of apoptotic chondrocytes and most prominently 'apoptosis resistance' in the inflamed synovial tissue. Tofacitinib, a JAK small molecule inhibitor, with selectivity for JAK2/JAK3 was approved by the United States Food and Drug Administration (US FDA) for the therapy of RA. Importantly, tofacitinib has demonstrated significant clinical efficacy for RA in the post-US FDA-approval surveillance period. Of note, the success of tofacitinib has spurred the development of JAK1, JAK2 and other JAK3-selective small molecule inhibitors, some of which have also entered the clinical setting, whereas other JAK inhibitors are currently being evaluated in RA clinical trials.

Keywords: Janus kinase; cytokine; rheumatoid arthritis; signal transducers and activators of transcription; signal transduction.

Figure 1.

JH domains and JAK3 phosphorylation sites. (Figure was originally published in Malemud and Pearlman). FERM, four-point.1-ezrin-radaxin-moesin domain; JAK, Janus kinase; JH, JAK homology; kinase-like, pseudokinase domain; SH2, Src homology domain; Tyr kinase, tyrosine kinase domain.

Figure 2.

The interaction of IL-6 with the IL-6Rα/gp130 complex activates JAK3 resulting in the phosphorylation of STAT3 (p-STAT3) (ON). SHP-1 is a phosphatase which regulates STAT phosphorylation by de-phosphorylating p-STAT3 (OFF). (Figure was originally published in Malemud and Pearlman^22). IL, interleukin; JAK, Janus kinase.