Defective JAK-STAT Pathway Signaling Contributes to Autoimmune Diseases

Abstract

Here, we systematically review the published literature indicating that aberrant regulation of Janus kinase/signal transducers and activators of transcription (JAK-STAT) signaling was associated with the autoimmune disorders, rheumatoid arthritis, systemic lupus erythematosus, psoriasis/psoriatic arthritis, multiple sclerosis, inflammatory bowel diseases, and ankylosing spondylitis. The autoimmune disorders discussed in this review are characterized by several alterations resulting in abnormal JAK-STAT signaling. These abnormalities in JAK-STAT signaling include (1) constitutive activation of both the interleukin-6(IL-6)/interleukin-6 receptor (IL-6R) canonical and IL-6 trans-signaling pathway, the latter involving soluble IL-6R; (2) the hyperactivation of JAK/STAT signaling as a response to the significantly elevated levels of pro-inflammatory “immunocytokines”, exemplified by IL-6, IL-15, IL-17, IL-23, interferon-γ; and (3) the reduced activity of the negative regulators of JAK-STAT signaling, including suppressor of cytokine signaling and protein inhibitor of activated STATs as well as protein tyrosine phosphatases-1, -2, which was shown to inhibit STAT-signaling. The involvement of abnormal JAK-STAT signaling in autoimmune disorders has led to the development of JAK small molecule inhibitors (SMIs), such as tofacitinib, ruxolitinib, and baricitinib for the therapy of rheumatoid arthritis, psoriasis/psoriatic arthritis, and Crohn’s disease. However, the extent to which treatment of these diseases with JAK SMIs will result in blunting the “cross-talk” between the JAK-STAT signaling pathway and the other signaling pathways known to participate in autoimmune disorders remains to be determined, involving the mitogen-activated protein kinase pathway and the phosphatidylinositide/Akt/mechanistic target of rapamycin signaling pathway.