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Defective JAK-STAT Pathway Signaling Contributes to Autoimmune Diseases

  • Kinase Inhibitor (A Minden, Section Editor)
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Abstract

Purpose of Review

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.

Pertinent Findings

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.

Summary

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.

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Acknowledgements

The experimental results reported in Meszaros and Malemud (references 73 and 75) and Malemud et al. (references 13 and 118) were supported, in part, by contracts between Takeda Pharmaceuticals of North America and CWRU, and, Genentech/Roche and CWRU, the Visual Sciences Research Center funded by the National Eye Institute (P30-EY11373) and the National Institute of Childhood & Human Development (R01-HD061819; PI: Sam Mesiano, PhD).

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  1. Department of Medicine, Division of Rheumatic Diseases, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA

    Charles J. Malemud

  2. Department of Medicine, University Hospitals Cleveland Medical Center, Foley Medical Building, 2061 Cornell Road, Room 207, Cleveland, OH, 44106-5076, USA

    Charles J. Malemud

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Correspondence to Charles J. Malemud.

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Malemud, C.J. Defective JAK-STAT Pathway Signaling Contributes to Autoimmune Diseases. Curr Pharmacol Rep 4, 358–366 (2018). https://doi.org/10.1007/s40495-018-0151-4

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