Within a Complex Disease Landscape, Common Intracellular Signaling Proteins Underlie Diverse Inflammatory Pathways
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INTRACELLULAR SIGNALING PROTEINS IN RA
Over the last several decades, researchers have identified a diverse array of immune cells, cytokines, and other inflammatory mediators as important contributors to the pathogenesis of rheumatoid arthritis (RA). While these numerous actors contribute to different pathological processes in RA, many are known to activate common intracellular signaling pathways.1-4 Extracellular signals—such as those triggered by cytokines binding to their receptors—can generate important events downstream that lead to upregulation of gene expression and, ultimately, the production of more inflammatory proteins. Advances in our understanding of the complex pathogenesis of RA have pointed to these downstream signaling cascades as fundamental drivers of disease.5 (Figure 1)
Immune cells contain intracellular signaling proteins that help to propagate signal transduction. Of the assemblage of proteins involved in transmitting extracellular signals across the plasma membrane and to the nucleus, messenger systems operating via mitogen-activated protein kinase (MAPK), nuclear factor-kappa B (NF-κB), and Janus kinase (JAK) are among those involved in transmitting downstream signals initiated by inflammatory mediators important in RA.1,6 Bruton’s tyrosine kinase (BTK), an integral intracellular signaling protein that functions downstream of the B-cell receptor (BCR), has also garnered attention due to its involvement in multiple cell populations and RA-related cascades.1,4 Recent research has highlighted the importance of these key signal transduction proteins in perpetuating a cycle of inflammation.5
CRITICAL INTRACELLULAR PROTEINS:
A SPOTLIGHT ON JAKS
The cytokine-activated JAK family of receptor-associated tyrosine kinases are essential intracellular proteins that can affect downstream responses for a broad collection of cytokines.2,3 Due to their central role in mediating downstream effects of key cytokines implicated in RA pathogenesis, JAK proteins have been compelling therapeutic targets, validated by clinical trials that have resulted in FDA approval of 2 agents to date for the treatment of RA.7 Members of the JAK family, consisting of JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2), orchestrate signals driven by type I and II cytokines, growth factors, and hormones alike.3 Many cytokines important in RA activate JAK-mediated pathways, including interleukin (IL)-4, IL-6, IL-15, IL-21, IL-23, interferon (IFN)-α, IFN-β, IFN-γ, and granulocyte-macrophage colony-stimulating factor (GM-CSF).2,8
JAKs coordinate downstream cascades in pairs or more. They bind to the intracellular domains of cytokine receptors, which are comprised of multiple subunits.9 While some of the intricacies of JAK signaling remain unclear, it is thought that upon cytokine binding, receptor subunits re-orient, positioning bound JAKs in such a way that allows for their cross-phosphorylation and activation. Activated JAKs then phosphorylate their associated receptors, which creates sites for additional proteins—such as signal transducer and activator of transcription (STAT) proteins—to bind.9 (Figure 2) Once bound, STAT proteins are subsequently phosphorylated by JAKs, resulting in STAT protein dimers that travel to the nucleus to influence gene expression.2,3 In RA, JAK-STAT signaling can lead to an induction of inflammatory gene expression and the subsequent production of cytokines and other degradative mediators.5
The various JAK proteins are known to associate with different cytokine receptors; of the JAKs involved in RA, the JAK2/JAK2 pair influences the signaling of cytokines and growth factors such as GM-CSF and erythropoietin, and the JAK1/JAK3 pair is important for cascades associated with common γ-chain cytokines such as IL-4 and IL-15. Pairings that involve JAK1 are also involved in transmitting IFN- and IL-6–initiated signals.2,8,10 IL-6 stands out as a central promoter of disease and is involved throughout its course. IL-6 is thought to play a hand in transforming the joint synovium by contributing to T-cell migration and activation, B-cell activation, as well as downstream inflammation.1,11 Together with tumor necrosis factor (TNF)-α, IL-6 can also mediate the breakdown of bone.1,11 Cytokine signaling via JAKs is also thought to contribute to pain1 and C-reactive protein production3, as well as joint destruction2 (Figure 3) .
In addition to orchestrating cytokine-driven signals, activating JAK/STAT pathways can lead to the production of cytokines important for RA. While TNF-α, IL-1, and IL-17 do not employ JAK proteins within downstream signaling cascades, JAK signaling by way of other cytokines can lead to the production of TNF-α, IL-1, and IL-17.2
Given their pervasive expression and various roles in RA pathogenesis, therapeutic strategies targeting these proteins present a means of targeting a broader array of disease-instigating cytokines and inflammatory mediators than do agents targeting select cytokines alone. It is important to note that outside of disease, the ubiquity of JAKs in immune and hematopoietic cells implicates them in other important physiological processes. For instance, the JAK2/JAK2 pair mediates the downstream effects of erythropoietin and plays a critical role in regulating red blood cell development.2,3,5 Thus, in harnessing JAKs as therapeutic targets, selective targeting of one JAK isomer may be important in mitigating undesirable effects on normal functions.
UNMET NEED IN RA
Multiple therapeutic strategies can be exploited to manage RA. Homing in on targets such as extracellular cytokine signals and cell-cell interactions has led to advances in the understanding of RA.12 This understanding of disease pathogenesis has catalyzed the development of targeted therapeutics that act specifically on drivers of disease, leading to an impressive portfolio of therapies targeted toward both extracellular cytokine signals and cell-cell interactions.1,12 While such progress has led to dramatic improvements in RA treatment, outcomes remain suboptimal for some patients. For instance, some patients continue to experience pain, fatigue, and disease activity despite treatment; nearly 50% of patients treated with disease-modifying antirheumatic drugs fail to achieve minimal residual disease activity, as indicated by the Health Assessment Questionnaire, or (HAQ).13
Intracellular signaling proteins stand out against the complex inflammatory landscape of RA owing to their influence on a broad range of actors. Out of the many intracellular signaling pathways known to transmit cytokine-driven signals, JAKs have emerged as validated therapeutic targets in RA. These intracellular proteins function in pairs or more and can associate with STATs to induce changes in gene expression. Targeting JAK proteins is a promising strategy for influencing multiple cytokine pathways with a single therapy. Ongoing research will yield a deeper appreciation of the components of intracellular signaling cascades and arm physicians with additional tools to manage RA.
- McInnes IB, Schett G. Pathogenetic insights from the treatment of rheumatoid arthritis. Lancet. 2017;389(10086):2328–2337.
- Schwartz DM, Bonelli M, Gadina M, O’Shea JJ. Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases. Nat Rev Rheumatol. 2016;12(1):25-36.
- Schwartz DM, Kanno Y, Villarino A, Ward M, Gadina M, O’Shea JJ. JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. Nat Rev Drug Discov. 2017;16(12):843-862.
- Whang JA, Chang BY. Bruton’s tyrosine kinase inhibitors for the treatment of rheumatoid arthritis. Drug Discov Today. 2014;19(8):1200-1204.
- Hodge JA, Kawabata TT, Krishnaswami S, et al. The mechanism of action of tofacitinib—an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. Clin Exp Rheumatol. 2016;34(2):318-328.
- Sweeney SE, Firestein GS. Primer: signal transduction in rheumatic disease—a clinician’s guide. Nat Clin Pract Rheumatol. 2007;3(11):651-660.
- Bellinvia S, Edwards CJ. JAK inhibitors in the treatment algorithm of rheumatoid arthritis: a review. EMJ Rheumatol. 2018;5(1):59-65.
- Ridgley LA, Anderson AE, Pratt AG. What are the dominant cytokines in early rheumatoid arthritis? Curr Opin Rheumatol. 2018;30(2):207-214.
- Babon JJ, Lucet IS, Murphy JM, Nicola NA, Varghese LN. The molecular regulation of Janus kinase (JAK) activation. Biochem J. 2014;462(1):1-13.
- Clark JD, Flanagan ME, Telliez JB. Discovery and development of Janus kinase (JAK) inhibitors for inflammatory diseases. J Med Chem. 2014;57(12):5023-5038.
- McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011;365(23):2205-2219.
- Parmentier JM, Voss J, Graff C, et al. In vitro and in vivo characterization of the JAK1 selectivity of upadacitinib (ABT-494). BMC Rheumatol. 2018;2:23. doi:10.1186/s41927-018-0031-x.
- Taylor PC, Moore A, Vasilescu R, Alvir J, Tarallo M. A structured literature review of the burden of illness and unmet needs in patients with rheumatoid arthritis: a current perspective. Rheumatol Int. 2016;36(5):685–695.
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