Activation of c-Jun N-Terminal Kinase, a Potential Therapeutic Target in Autoimmune Arthritis

Abstract

The c-Jun-N-terminal kinase (JNK) is a critical mediator involved in various physiological processes, such as immune responses, and the pathogenesis of various diseases, including autoimmune disorders. JNK is one of the crucial downstream signaling molecules of various immune triggers, mainly proinflammatory cytokines, in autoimmune arthritic conditions, mainly including rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis. The activation of JNK is regulated in a complex manner by upstream kinases and phosphatases. Noticeably, different subtypes of JNKs behave differentially in immune responses. Furthermore, aside from biologics targeting proinflammatory cytokines, small-molecule inhibitors targeting signaling molecules such as Janus kinases can act as very powerful therapeutics in autoimmune arthritis patients unresponsiveness to conventional synthetic antirheumatic drugs. Nevertheless, despite these encouraging therapies, a population of patients with an inadequate therapeutic response to all currently available medications still remains. These findings identify the critical signaling molecule JNK as an attractive target for investigation of the immunopathogenesis of autoimmune disorders and for consideration as a potential therapeutic target for patients with autoimmune arthritis to achieve better disease control. This review provides a useful overview of the roles of JNK, how JNK is regulated in immunopathogenic responses, and the potential of therapeutically targeting JNK in patients with autoimmune arthritis.

Keywords: arthritis; autoimmune; c-Jun N-terminal kinase; inflammation.

Figure 1

Activation of JNK by proinflammatory cytokines TNF-α and IL-17 leading to autoimmune arthritis. Binding of proinflammatory cytokine TNF-α or IL-17 to its receptor induces activation of JNK-AP-1 leading to autoimmune arthritis. Along the signaling pathways, many adaptors and kinases are involved. The sequences of activation are indicated with arrows. The TNF-α- and IL-17-mediated signaling pathways are shown in red color and green color, respectively. The common pathway shared by both TNF-α and IL-17 signals is illustrated in black color. Abbreviations: TNF-α, tumor necrosis factor-alpha; TNF-αR, TNF-α receptor; IL-17, interleukin-17; TNFR1, TNF receptor 1; TRADD, TNFR1-associated DD protein; RIPK1, receptor interacting serine/threonine-protein kinase 1; GCK, germinal center kinase; HPK, hematopoietic progenitor kinase; HGK, HPK1/GCK-like kinase; GLK, GCK-like kinase; ACT1, also known as CIKS (connection to inhibitor of κB (IκB) kinase and stress-activated protein kinases); HGK, HPK/GCK-like kinase; PKC-θ, protein kinase C-θ; TRAF2, TNFR-associated factor; TAK1, transforming growth factor-beta (TGF-β)-activated kinase 1; ASK1, apoptosis signal-regulating kinase 1; TPL2, tumor progression locus 2; MAPK4K, MAP kinase kinase kinase kinase; MAPK3K, MAP kinase kinase kinase; MAP2K, MAP kinase kinase; MAPK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase; MEKK1, MAPK/ERK kinase kinase 1; MKK, mitogen-activated protein kinase kinase; AP-1, activator protein-1; JNK: c-Jun N-terminal Kinase.