The advent of biologic agents targeted against tumor necrosis factor-α (TNF-α) and interleukin 1 (IL-1) receptor has successfully suppressed inflammation in many individuals with rheumatoid arthritis (RA), but 60% of patients have at least some evidence of persistent disease1; moreover, the majority relapse when treatment is withdrawn. This has prompted research into alternative ways to suppress disease activity. The hematopoietin family of cytokines, which includes several postulated to have roles in RA (eg, interferons, IL-6, IL-2, IL-7, IL-12, IL-15) bind to Type I and II cytokine receptors and signal through the janus kinase-signal transducers and activators of transcription (Jak-STAT) pathway (Table 1) 2, 3. Therefore, a better understanding of Jak-STAT activation within the rheumatoid synovium may allow for development of novel therapeutic agents. In addition, these agents would have potential for oral bioavailability because they are targeted against small proteins4. Only 4 mammalian Jak have been identified—Jak1, Jak2, Tyk2, and Jak3. The first 3 are widely expressed, while Jak3 expression is essentially limited to hematopoietic cell lines. The STAT family has 7 identified members (STAT1, 2, 3, 4, 5a, 5b, and 6), and their recruitment is a critical component of inducing cell-specific responses2.

Briefly, Jak-STAT signaling occurs when hematopoietins bind to cytokine receptors, initiating a conformational change in the receptor. This brings Jak into apposition, resulting in transphosphorylation and subsequent activation. Once activated, Jak mediate phosphorylation of specific tyrosine residues. STAT and other molecules that recognize these phosphorylated sites are recruited to the receptor and undergo activation by Jak-driven tyrosine phosphorylation. The activated STAT then dissociate, undergo dimerization in the cytoplasm, translocate to the nucleus, and bind to members of GAS (γ-activated site) enhancers (Figure 1) 2. Recent studies have suggested that the predominant cytoplasmic distribution of STAT in resting cells may reflect a steadystate process5.