Novel strategies for inhibition of the p38 MAPK pathway

Zhang, Jiyan; Shen, Beifen; Lin, Anning

doi:10.1016/j.tips.2007.04.008

Cited by 141 publications

(120 citation statements)

References 102 publications

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“…However, despite some positive results, 40 global inhibition of p38 activity is associated with side effects, such as infection and gastrointestinal disturbances, [41][42][43] possibly because of the ubiquitous expression of p38 and its large variety of functions. 44,45 Our data provide direct genetic evidence that T-cell p38 activated in response to TCR signaling contributes to inflammatory autoimmune responses. Because the TCR activates p38 by a mechanism distinct from other receptors and stresses, these results raise the possibility that specific interference with the alternative p38 activation pathway might be beneficial in inflammatory autoimmune conditions.…”

Section: Role Of Tcr-induced P38 Activity In Autoimmunity 3287mentioning

confidence: 70%

Lack of the T cell–specific alternative p38 activation pathway reduces autoimmunity and inflammation

Jirmanova

Torchia

Sarma

et al. 2011

Blood

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Stimulation via the T-cell receptor (TCR) activates p38␣ and p38␤ by phosphorylation of p38 Tyr-323 (p38 Y323 ). Here we characterize knockin mice in which p38␣ and/or ␤ Tyr-323 has been replaced with Phe. We find that p38␣ accounts for twothirds and p38␤ the remainder of TCRinduced p38 activation. T cells from double knockin mice (p38␣␤ Y323F ) had defects in TCR-mediated proliferation and Th1 and Th17 skewing, the former corresponding with an inability to sustain T-bet expression. Introduction of p38␣ Y323F into Gadd45␣-deficient mice, in which the alternative p38 pathway is constitutively active, reversed T-cell hyperproliferation and autoimmunity. Furthermore, p38␣␤ Y323F mice had delayed onset and reduced severity of the inflammatory autoimmune diseases collagen-induced arthritis and experimental autoimmune encephalomyelitis. Thus, T cell-specific alternative activation of p38 is an important pathway in T-cell proliferation, Th skewing, and inflammatory autoimmunity, and may be an attractive tissuespecific target for intervention in these processes. (Blood. 2011;118(12):3280-3289)

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Section: Role Of Tcr-induced P38 Activity In Autoimmunity 3287mentioning

confidence: 70%

Lack of the T cell–specific alternative p38 activation pathway reduces autoimmunity and inflammation

Jirmanova

Torchia

Sarma

et al. 2011

Blood

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“…All of this evidence strongly indicates a pivotal role of miR125b-dependent repression in negatively regulating p38␣ activity in UVtreated cells. p38 is a family of MAPKs consisting of four isoforms: p38␣, p38␤, p38␦, and p38␥ (36). Both p38␣ and p38␤ can be activated by UV exposure; however, their roles in mediating cellular apoptotic response to UV treatment may be distinct.…”

Section: Discussionmentioning

confidence: 99%

NF-κB-dependent MicroRNA-125b Up-regulation Promotes Cell Survival by Targeting p38α upon Ultraviolet Radiation

Tan

Niu

Shi

et al. 2012

Journal of Biological Chemistry

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Background: UV radiation-induced miRNA expression modulates cellular stress response. Results: UV up-regulates miR-125b expression via ATM-dependent NF-B activation, which represses p38␣ expression. Conclusion: UV-induced miR-125b prevents prolonged p38␣ activation and thereby promotes cell survival. Significance: Up-regulation of miR-125b serves as a negative feedback mechanism to control p38␣ activity upon UV radiation, which may contribute to tumorigenesis of skin cancer.

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“…This finding is important because collagen-induced arthritis in mice can be inhibited by a variety of immune modulators. In addition, previous compounds shown to have efficacy in the rodent models of arthritis had significant off-target activity that could have contributed to the disease modification and adverse side effects (Fabian et al, 2005;Goldstein and Gabriel, 2005;Zhang et al, 2007). However, it is noteworthy that in a recent phase II trial of pamapimod, elevation of liver transamidase levels and C max -related dizziness in some patients was reported (Cohen et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Pamapimod, a Novel p38 Mitogen-Activated Protein Kinase Inhibitor: Preclinical Analysis of Efficacy and Selectivity

Hill¹,

Dabbagh²,

Phippard³

et al. 2008

J Pharmacol Exp Ther

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P38␣ is a protein kinase that regulates the expression of inflammatory cytokines, suggesting a role in the pathogenesis of diseases such as rheumatoid arthritis (RA) or systemic lupus erythematosus. Here, we describe the preclinical pharmacology of pamapimod, a novel p38 mitogen-activated protein kinase inhibitor. Pamapimod inhibited p38␣ and p38␤ enzymatic activity, with IC 50 values of 0.014 Ϯ 0.002 and 0.48 Ϯ 0.04 M, respectively. There was no activity against p38␦ or p38␥ isoforms. When profiled across 350 kinases, pamapimod bound only to four kinases in addition to p38. Cellular potency was assessed using phosphorylation of heat shock protein-27 and c-Jun as selective readouts for p38 and c-Jun NH 2 -terminal kinase (JNK), respectively. Pamapimod inhibited p38 (IC 50 , 0.06 M), but inhibition of JNK was not detected. Pamapimod also inhibited lipopolysaccharide (LPS)-stimulated tumor necrosis factor (TNF) ␣ production by monocytes, interleukin (IL)-1␤ production in human whole blood, and spontaneous TNF␣ production by synovial explants from RA patients. LPS-and TNF␣-stimulated production of TNF␣ and IL-6 in rodents also was inhibited by pamapimod. In murine collagen-induced arthritis, pamapimod reduced clinical signs of inflammation and bone loss at 50 mg/kg or greater. In a rat model of hyperalgesia, pamapimod increased tolerance to pressure in a dose-dependent manner, suggesting an important role of p38 in pain associated with inflammation. Finally, an analog of pamapimod that has equivalent potency and selectivity inhibited renal disease in lupus-prone MRL/lpr mice. Our study demonstrates that pamapimod is a potent, selective inhibitor of p38␣ with the ability to inhibit the signs and symptoms of RA and other autoimmune diseases.

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Novel strategies for inhibition of the p38 MAPK pathway

Cited by 141 publications

References 102 publications

Lack of the T cell–specific alternative p38 activation pathway reduces autoimmunity and inflammation

Lack of the T cell–specific alternative p38 activation pathway reduces autoimmunity and inflammation

NF-κB-dependent MicroRNA-125b Up-regulation Promotes Cell Survival by Targeting p38α upon Ultraviolet Radiation

Pamapimod, a Novel p38 Mitogen-Activated Protein Kinase Inhibitor: Preclinical Analysis of Efficacy and Selectivity

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