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.

Anti-Osteogenic Effect of Danshensu in Ankylosing Spondylitis: An in Vitro Study Based on Integrated Network Pharmacology

“…The ERK and MAPK pathways were also related to most AS targets of Danshensu. The MAPK pathway including ERK, JNK and p38 pathways, is involved in inflammatory signaling, regulation of cell proliferation and differentiation, and activation of the immune system ( Lai et al, 2020 ). The ERK1/2, JNK, and p38 pathways regulate osteoblast differentiation ( Chen et al, 2016 ), and inhibition of MAPK signaling was shown to reduce the expression levels of ALP and OCN ( Wang et al, 2019 ).…”

Where traditional Chinese medicine meets Western medicine in the prevention of rheumatoid arthritis

“…MAPKs phosphorylate a variety of intracellular proteins, including transcription factors that consequently regulate the expression of genes involved in cell proliferation, differentiation, survival, cellular stress and inflammatory responses. MAPKs contribute to the production of the inflammatory cytokines, chemokines, prostaglandins, MMPs and growth factors involved in joint inflammation and destruction and are important players in the RA pathogenesis [42][43][44]. The therapeutic potential of MAPKs as drug targets has been clearly demonstrated using specific inhibitors in experimental models of arthritis [45][46][47].…”

Design, synthesis and biological evaluation of novel O-substituted tryptanthrin oxime derivatives as c-Jun N-terminal kinase inhibitors

“…Although the structure and sequences of all JNKs are similar, containing well conserved features observed in other MAPKs, JNK1 and JNK3 closely resemble each other, with JNK2 containing sequence differences in the kinase domain ( Gupta et al, 1996 ). Despite the multifaceted role of JNKs in cell signaling, JNK has still been viewed as a promising target for several disease areas ( Lai et al, 2020 ; Yung and Giacca, 2020 ; Abdelrahman et al, 2021 ). Our interest comes from its role in mediating inflammatory and immunological responses ( Lai et al, 2020 ; Chen et al, 2021 ).…”

“…Despite the multifaceted role of JNKs in cell signaling, JNK has still been viewed as a promising target for several disease areas ( Lai et al, 2020 ; Yung and Giacca, 2020 ; Abdelrahman et al, 2021 ). Our interest comes from its role in mediating inflammatory and immunological responses ( Lai et al, 2020 ; Chen et al, 2021 ). Indeed, JNK inhibition has been demonstrated to downregulate the production of several proinflammatory transcription factors and cytokines ( Kaminska et al, 2009 ; Lai et al, 2020 ).…”

“…Our interest comes from its role in mediating inflammatory and immunological responses ( Lai et al, 2020 ; Chen et al, 2021 ). Indeed, JNK inhibition has been demonstrated to downregulate the production of several proinflammatory transcription factors and cytokines ( Kaminska et al, 2009 ; Lai et al, 2020 ). Due to the physiological isoform distribution within the body, therapeutic selectivity between the JNK isoforms could have major therapeutic benefits.…”