MK2: a novel molecular target for anti-inflammatory therapy

Duraisamy, Senthil; Bajpai, Malini; Bughani, Usha; Dastidar, Sunanda G.; Ray, Abhijit; Chopra, Puneet

doi:10.1517/14728222.12.8.921

Cited by 66 publications

(40 citation statements)

References 102 publications

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“…p38 inhibitors have been explored as potential anti-inflammatory agents in a number of diseases; however, none of these compounds has yet to be licensed due to problems with efficacy or tolerability (62). For that reason, focus has shifted to MK2 kinase, a substrate of p38 which is more narrowly expressed and is felt to be more specifically involved in stressinduced inflammation (34,63). pMK2, whose precursor is p38, belongs to the calcium-calmodulin kinase superfamily (64).…”

Section: Discussionmentioning

confidence: 99%

“…pMK2, whose precursor is p38, belongs to the calcium-calmodulin kinase superfamily (64). After activation of p38 by a variety of stressors, pMK2 phosphorylates specific molecules which regulate the actin cytoskeleton and stabilize cytokine mRNA transcripts (34,65,66). mRNA transcripts for IL-8 and TNF-␣ can then mediate a number of downstream effects, including neutrophil chemotaxis, vasodilation, tissue edema, and cellular apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…mRNA transcripts for IL-8 and TNF-␣ can then mediate a number of downstream effects, including neutrophil chemotaxis, vasodilation, tissue edema, and cellular apoptosis. Several MK2 kinase inhibitors are currently in development for treatment of inflammatory diseases, and it is hoped that these compounds will retain the anti-inflammatory activity of p38 inhibitors while lacking the toxicities that may relate essential noninflammatory p38 activities (30,34). We find that TcdA and TcdB cause p38-dependent activation of MK2 and demonstrate that MK2 inhibition in vitro completely blocks toxin-induced IL-8 release from both enterocytes and monocytes despite the observation that MK2 inhibition does not affect the toxin-induced effects on the cell.…”

Section: Discussionmentioning

confidence: 99%

“…Upon MK2-induced phosphorylation, Hsp27 undergoes a conformational change, shifting from large multimers to dimers to affect chaperone function and interactions with the actin cytoskeleton (27,28). Like p38 kinase, which is the target of several novel anti-inflammatory agents, MK2 kinase is a target of several anti-inflammatory drug discovery programs (29)(30)(31)(32)(33)(34).…”

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confidence: 99%

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MAPK-Activated Protein Kinase 2 Contributes to Clostridium difficile-Associated Inflammation

et al. 2013

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Clostridium difficile infection (CDI) results in toxin-induced epithelial injury and marked intestinal inflammation. Fecal markers of intestinal inflammation correlate with CDI disease severity, but regulation of the inflammatory response is poorly understood. Previous studies demonstrated that C. difficile toxin TcdA activates p38 kinase in tissue culture cells and mouse ilium, resulting in interleukin-8 (IL-8) release. Here, we investigated the role of phosphorylated mitogen-activated protein kinase (MAPK)-activated protein kinase (MK2 kinase, pMK2), a key mediator of p38-dependent inflammation, in CDI. Exposure of cultured intestinal epithelial cells to the C. difficile toxins TcdA and TcdB resulted in p38-dependent MK2 activation. Toxininduced IL-8 and GRO␣ release required MK2 activity. We found that p38 and MK2 are activated in response to other actin-disrupting agents, suggesting that toxin-induced cytoskeleton disruption is the trigger for kinase-dependent cytokine response. Phosphorylated MK2 was detected in the intestines of C. difficile-infected hamsters and mice, demonstrating for the first time that the pathway is activated in infected animals. Furthermore, we found that elevated pMK2 correlated with the presence of toxigenic C. difficile among 100 patient stool samples submitted for C. difficile testing. In conclusion, we find that MK2 kinase is activated by TcdA and TcdB and regulates the expression of proinflammatory cytokines. Activation of p38-MK2 in infected animals and humans suggests that this pathway is a key driver of intestinal inflammation in patients with CDI.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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MAPK-Activated Protein Kinase 2 Contributes to Clostridium difficile-Associated Inflammation

et al. 2013

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“…They survive LPS-induced endotoxic shock due to a reduction of the secretion of TNF-α by almost 90% [75]. MK2 has been considered as a key molecule participating in host defense against intracellular bacteria through regulation of both TNF-α and IFN-γ production [76,77].…”

Section: P38 Mapk In Psoriasis and Psoriatic Arthritismentioning

confidence: 99%

The Role of p38 MAPK in Rheumatic Diseases

Mavropoulos¹,

Κουτσουμπασ²,

Bogdanos³

2015

ITI

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Abstract-p38 mitogen activated protein kinase (p38 MAPK) signaling appears to play a significant role in the regulation of immune-mediated inflammatory responses and therefore has been linked with several autoimmune diseases. This review discusses the current data regarding the involvement of p38 MAP in rheumatic diseases characterized by arthritis, with special attention in psoriatic arthritis, an arthritis with no apparent autoimmune features, and rheumatoid arthritis, an arthritis with apparent autoimmune features.

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An Angle on MK2 Inhibition—Optimization and Evaluation of Prevention of Activation Inhibitors

et al. 2019

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The mitogen‐activated protein kinase p38α pathway has been an attractive target for the treatment of inflammatory conditions such as rheumatoid arthritis. While a number of p38α inhibitors have been taken to the clinic, they have been limited by their efficacy and toxicological profile. A lead identification program was initiated to selectively target prevention of activation (PoA) of mitogen‐activated protein kinase‐activated protein kinase 2 (MK2) rather than mitogen‐ and stress‐activated protein kinase 1 (MSK1), both immediate downstream substrates of p38α, to improve the efficacy/safety profile over direct p38α inhibition. Starting with a series of pyrazole amide PoA MK2 inhibitor leads, and guided by structural chemistry and rational design, a highly selective imidazole 9 (2‐(3′‐(2‐amino‐2‐oxoethyl)‐[1,1′‐biphenyl]‐3‐yl)‐N‐(5‐(N,N‐dimethylsulfamoyl)‐2‐methylphenyl)‐1‐propyl‐1H‐imidazole‐5‐carboxamide) and the orally bioavailable imidazole 18 (3‐methyl‐N‐(2‐methyl‐5‐sulfamoylphenyl)‐2‐(o‐tolyl)imidazole‐4‐carboxamide) were discovered. The PoA concept was further evaluated by protein immunoblotting, which showed that the optimized PoA MK2 compounds, despite their biochemical selectivity against MSK1 phosphorylation, behaved similarly to p38 inhibitors in cellular signaling. This study highlights the importance of selective tool compounds in untangling complex signaling pathways, and although 9 and 18 were not differentiated from p38α inhibitors in a cellular context, they are still useful tools for further research directed to understand the role of MK2 in the p38α signaling pathway.

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MK2: a novel molecular target for anti-inflammatory therapy

Cited by 66 publications

References 102 publications

MAPK-Activated Protein Kinase 2 Contributes to Clostridium difficile-Associated Inflammation

MAPK-Activated Protein Kinase 2 Contributes to Clostridium difficile-Associated Inflammation

The Role of p38 MAPK in Rheumatic Diseases

An Angle on MK2 Inhibition—Optimization and Evaluation of Prevention of Activation Inhibitors

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