Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases

Abstract

Cytokines are major drivers of autoimmunity, and biologic agents targeting cytokines have revolutionized the treatment of immune-mediated diseases. Despite the effectiveness of these drugs, they do not induce complete remission in all patients, prompting the development of alternative strategies - including targeting of intracellular signal transduction pathways downstream of cytokines. Many cytokines that bind type I and type II cytokine receptors are critical regulators of immune-mediated diseases and employ the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathway to exert their effect. Pharmacological inhibition of JAKs blocks the actions of type I/II cytokines, and within the past 3 years therapeutic JAK inhibitors, or Jakinibs, have become available to rheumatologists. Jakinibs have proven effective for the treatment of rheumatoid arthritis and other inflammatory diseases. Adverse effects of these agents are largely related to their mode of action and include infections and hyperlipidemia. Jakinibs are currently being investigated for a number of new indications, and second-generation selective Jakinibs are being developed and tested. Targeting STATs could be a future avenue for the treatment of rheumatologic diseases, although substantial challenges remain. Nonetheless, the ability to therapeutically target intracellular signalling pathways has already created a new paradigm for the treatment of rheumatologic disease.

Conflict of interest statement

Competing interests

J.OS. declares that he and the US Government receive royalties based on patents related to targeting Janus kinases. JOS and M.G. and the US Government have had longstanding Cooperative Research and Development Agreements with Pfizer, which produces tofacitinib, a Janus kinase inhibitor.

Figures

Figure 1

Cytokines are grouped into superfamilies based on shared structural elements of the receptors they bind. The major cytokine families are: the type I/II cytokines, the IL-1 family, the TNF family, the IL-17 cytokines, the RTK/SCF cytokines, the TGF-β family cytokines, and chemokines. The type I/II cytokine families signal through JAKs and STATs. When a cytokine binds to its cognate receptor, the receptor becomes activated. JAKs autophosphorylate and transphosphorylate, causing STATs to be recruited to the activated receptor where they, in turn, are phosphorylated. The STATs then dimerize and translocate to the nucleus where they initiate transcription. FDA-approved medications blocking the different classes of cytokine receptor are denoted in red. Abbreviations: JAK, Janus kinase; RTF, receptor tyrosine kinase; SCF, stem cell factor; STAT, TGF-β, transforming growth factor β.

Figure 2

Type I and II cytokines (red), which are blocked by JAKinibs, are major drivers of autoimmune diseases such as RA. Within the RA joint, FLSs are major sources of TNF, IL-1β, IL-6, and G-CSF. IL-6, along with IL1β, and IL-23, promotes the differentiation of pathogenic TH17 cells. Pathogenic TH17 cells produce the neutrophil growth factor GM-CSF. G-CSF and GM-CSF drive neutrophil-derived production of TNF and IL-1β. TH17 cells are also the major producers of IL-17. IL-17, TNF, and IL-1β induce production of MMPs and ADAMTS, which degrade the cartilage matrix. Similarly, production of the type I cytokine IL-12 by macrophages and DCs promotes the differentiation of pathogenic TH1 cells. TH1 cells produce IFN-γ, activates macrophages. IL-20 and other cytokines promote bone resorption by osteoclasts. DCs also produce IL-15, which promotes FLS survival and TH1 differentiation, and IL-21, which promotes TFH cell differentiation and antibody production. Abbreviations; ADAMTS, a disintegrin and metalloproteinase with thrombospondin motifs; DC, dendritic cell; FLS, fibroblast-like synoviocyte; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocuyte-macrophage colony-stimulating factor; IFN-γ, interferon-γ; MMP, matrix metalloproteinase; TFH cell, follicular helper T cell; TH17 cell, type 17 helper T cell.

Figure 3

JAKs are composed of several key domains including a tyrosine kinase domain, pseudokinase domain, FERM (band four-point-one, ezrin, radixin, moesin) domain, and an SH2 (Src homology 2) domain. The tyrosine kinase domain binds ATP hydrolyzing it to ADP and catalyzes both autophosphorylation and other substrates including STATs. Jakinibs bind to the pocket ordinarily occupied by ATP, thereby preventing JAKs from using ATP and phosphorylating their substrates.