JAK and STAT signaling molecules in immunoregulation and immune-mediated disease

Abstract

The discovery of the Janus kinase (JAK)-signal transducer and activator of transcripton (STAT) signaling pathway, a landmark in cell biology, provided a simple mechanism for gene regulation that dramatically advanced our understanding of the action of hormones, interferons, colony-stimulating factors, and interleukins. As we learn more about the complexities of immune responses, new insights into the functions of this pathway continue to be revealed, aided by technology that permits genome-wide views. As we celebrate the 20(th) anniversary of the discovery of this paradigm in cell signaling, it is particularly edifying to see how this knowledge has rapidly been translated to human immune disease. Not only have genome-wide association studies demonstrated that this pathway is highly relevant to human autoimmunity, but targeting JAKs is now a reality in immune-mediated disease.

Figure 1

Genetics links of cytokine signaling with human autoimmune disease. Although various animal models have implicated cytokines, their receptors, JAKs and STATs with autoimmune disease, genomewide association studies (GWAS) now show that these factors are truly relevant to human disease. This work shows that pathways that lead to STAT3 and STAT4 activation lie at the heart of many common autoimmune diseases Adapted from (Cho and Gregersen, 2011). AS – ankylosing spondylitis, IBD – inflammatory bowel disease; PBC –primary biliary cirrhosis, SLE – systemic lupus erythematosus.

Figure 2

Consequence of Jak inhibition on signaling by key immunoregulatory cytokines. A variety of JAKinibs have been developed with varying degrees of specificity for the different Jaks. The consequences of inhibiting each of the Jaks on these selected cytokines is depicted. Most inhibitors in clinical use inhibit more than one Jak; however, increasingly selective JAKinibs are in development. A selective Tyk2 inhibitor has yet to be reported.