Regulation of JNK by MKK‐7 in fibroblast‐like synoviocytes

Inoue, Tomoyuki; Hammaker, Deepa; Boyle, David L.; Firestein, Gary S.

doi:10.1002/art.21919

Cited by 48 publications

(53 citation statements)

References 28 publications

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“…JNK is thought to be important in extracellular matrix degradation. JNK is a critical MAPK pathway for IL-1-induced collagenase gene expression and regulation of MMP secretion in RASF [37][38][39]. Furthermore, JNK-1deficient osteoclast progenitors were unable to mature into bone-resorbing osteoclasts following exposure to receptor activator of nuclear factor-κB ligand (RANKL) [40].…”

Section: Discussionmentioning

confidence: 99%

Critical role for apoptosis signal-regulating kinase 1 in the development of inflammatory K/BxN serum-induced arthritis

Mnich

Blanner

et al. 2010

International Immunopharmacology

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Section: Discussionmentioning

confidence: 99%

Critical role for apoptosis signal-regulating kinase 1 in the development of inflammatory K/BxN serum-induced arthritis

Mnich

Blanner

et al. 2010

International Immunopharmacology

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“…JNK can be strongly activated in multiple cell types by LPS or inflammatory cytokines and regulates AP-1 transcription factor activity and the production of inflammatory cytokines (64,65). Previous studies demonstrated that MKK7, but not MKK4, is essential for IL-1-mediated JNK activation in cultured fibroblast-like synoviocytes (52). However, the functions of MKK4 in regulating the innate immune responses in the macrophages have not been fully defined.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-92a Negatively Regulates Toll-like Receptor (TLR)-triggered Inflammatory Response in Macrophages by Targeting MKK4 Kinase

Lai

Song

Liu

et al. 2013

Journal of Biological Chemistry

117

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Background: microRNAs (miRNAs) participate in innate immune responses. Results: miR-92a decreases rapidly in macrophages once stimulated with TLR ligands, and miR-92a controls inflammatory response by targeting MKK4/JNK/c-Jun pathway. Conclusion: TLR-mediated miR-92a reduction feedback enhances TLR-triggered inflammatory response. Significance: Our findings reveal a novel positive feedback loop in which TLR-reduced miR-92a expression functions to regulate the innate inflammatory responses.

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“…1). Because JNK is typically activated by MKK4 and MKK7 and both MKKs are phosphorylated in rheumatoid synovium (Sundarrajan et al, 2003;Inoue et al, 2006), binding affinities of IQ-1S toward these kinases were also determined. However, IQ-1S demonstrated only a low binding affinity for MKK4 (K d approximately 2.2 mM) and there was no affinity for MKK7.…”

Section: Inhibition Of Collagen-induced Arthritis By Iq-1smentioning

confidence: 99%

Anti-Inflammatory Effects and Joint Protection in Collagen-Induced Arthritis after Treatment with IQ-1S, a Selective c-Jun N-Terminal Kinase Inhibitor

Schepetkin

Kirpotina

Hammaker

et al. 2015

J Pharmacol Exp Ther

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c-Jun N-terminal kinases (JNKs) participate in many physiologic and pathologic processes, including inflammatory diseases. We recently synthesized the sodium salt of IQ-1S (11H-indeno[1,2-b]quinoxalin-11-one oxime) and demonstrated that it is a high-affinity JNK inhibitor and inhibits murine delayed-type hypersensitivity. Here we show that IQ-1S is highly specific for JNK and that its neutral form is the most abundant species at physiologic pH. Molecular docking of the IQ-1S syn isomer into the JNK1 binding site gave the best pose, which corresponded to the position of cocrystallized JNK inhibitor SP600125 (1,9-pyrazoloanthrone). Evaluation of the therapeutic potential of IQ-1S showed that it inhibited matrix metalloproteinase 1 and 3 gene expression induced by interleukin-1b in human fibroblast-like synoviocytes and significantly attenuated development of murine collagen-induced arthritis (CIA). Treatment with IQ-1S either before or after induction of CIA resulted in decreased clinical scores, and joint sections from IQ-1S-treated CIA mice exhibited only mild signs of inflammation and minimal cartilage loss compared with those from control mice. Collagen II-specific antibody responses were also reduced by IQ-1S treatment. By contrast, the inactive ketone derivative 11H-indeno[1,2-b]quinoxalin-11-one had no effect on CIA clinical scores or collagen II-specific antibody titers. IQ-1S treatment also suppressed proinflammatory cytokine and chemokine levels in joints and lymph node cells. Finally, treatment with IQ-1S increased the number of Foxp3 CD251 regulatory T cells in lymph nodes. Thus, IQ-1S can reduce inflammation and cartilage loss associated with CIA and can serve as a small-molecule modulator for mechanistic studies of JNK function in rheumatoid arthritis.

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Regulation of JNK by MKK‐7 in fibroblast‐like synoviocytes

Cited by 48 publications

References 28 publications

Critical role for apoptosis signal-regulating kinase 1 in the development of inflammatory K/BxN serum-induced arthritis

Critical role for apoptosis signal-regulating kinase 1 in the development of inflammatory K/BxN serum-induced arthritis

MicroRNA-92a Negatively Regulates Toll-like Receptor (TLR)-triggered Inflammatory Response in Macrophages by Targeting MKK4 Kinase

Anti-Inflammatory Effects and Joint Protection in Collagen-Induced Arthritis after Treatment with IQ-1S, a Selective c-Jun N-Terminal Kinase Inhibitor

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