Role of p38 Mitogen-Activated Protein Kinase in Chemokine-Induced Emigration and Chemotaxis In Vivo

Cara, Denise Carmona; Kaur, Jaswinder; Forster, Melanie; McCafferty, Donna–Marie; Kubes, Paul

doi:10.4049/jimmunol.167.11.6552

Cited by 115 publications

(114 citation statements)

References 36 publications

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“…This points to a general inhibition of synovial inflammation by p38 MAPK blockade rather than specific effects on single cell types, and suggests that p38 MAPK activation is a critical factor in the severity of synovial inflammation. It is compatible with our previous finding of overexpression of p38 MAPK in endothelial cells, allowing us to speculate that p38 MAPK blockade may affect transendothelial migration (27). Furthermore, the observed reduction in the expression of downstream cytokines such as IL-1 and RANKL is also in accordance with the reduction in the inflammatory response.…”

Section: Discussionsupporting

confidence: 91%

Activation of p38 MAPK is a key step in tumor necrosis factor–mediated inflammatory bone destruction

Zwerina¹,

Hayer²,

Redlich³

et al. 2006

Arthritis & Rheumatism

133

107

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Objective. To investigate whether activation of p38 MAPK is a crucial signaling factor in inflammatory bone destruction mediated by tumor necrosis factor (TNF). Mice overexpressing TNF were treated with 2 different inhibitors of p38 MAPK, and the effect of this treatment on joint inflammation and structural damage was assessed.Methods. Human TNF-transgenic mice received systemic treatment with 2 different p38 MAPK inhibitors (RO4399247 and AVE8677). Treatment was started at the time of symptom onset and lasted for 6 weeks. Mice were assessed for clinical signs of arthritis, bone erosion, and cartilage damage. In addition, the effect of these inhibitors on osteoclast generation in vitro and in vivo was assessed.Results. Both p38 MAPK inhibitors significantly reduced clinical signs of TNF-mediated arthritis. This was attributable to reducing synovial inflammation by 50% without affecting the cellular composition of the infiltrate. Synovial expression of interleukin-1 and RANKL was reduced upon p38 MAPK blockade, and activation of the molecular target MAPK-activated protein kinase 2 (MAPKAP-2) was also inhibited. Proteoglycan loss of articular cartilage was reduced by 50%, although p38 MAPK inhibition did not change matrix molecule synthesis by cultivated chondrocytes. Importantly, bone loss was almost completely prevented by p38 MAPK inhibition. The numbers of synovial osteoclasts and precursors were dramatically reduced, and both p38 MAPK inhibitors also inhibited in vitro osteoclastogenesis at micromolar concentrations and blocked activation of MAPKAP-2 as well as differentiation markers in cultured osteoclast precursors.Conclusion. These results suggest the major importance of p38 MAPK for TNF-mediated inflammatory bone destruction in arthritis and suggest that inhibition of p38 MAPK might be an important tool for reducing structural damage in rheumatoid arthritis.

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Section: Discussionsupporting

confidence: 91%

Activation of p38 MAPK is a key step in tumor necrosis factor–mediated inflammatory bone destruction

Zwerina¹,

Hayer²,

Redlich³

et al. 2006

Arthritis & Rheumatism

133

107

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“…Indeed, several reports have shown that SAPK2/p38 is involved in chemokine-induced chemotaxis of cells (16,34,70,71). Our study also presents evidence that SAPK2/p38 and SAPK1/JNK1, but not ERKs, intervene in the control of MCP-1-induced MonoMac6 migration.…”

Section: Discussionsupporting

confidence: 68%

Soluble Fractalkine Prevents Monocyte Chemoattractant Protein-1-Induced Monocyte Migration via Inhibition of Stress-Activated Protein Kinase 2/p38 and Matrix Metalloproteinase Activities

Vitale

Schmid-Alliana

Breuil

et al. 2004

The Journal of Immunology

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In this study, we address the question of the cross-talk between two chemokines that are cosecreted during inflammation, namely monocyte chemoattractant protein-1 (MCP-1) and soluble fractalkine (s-FKN), toward monocyte migration. We found that s-FKN fails to induce MonoMac6 cell migration per se. Interestingly, this chemokine antagonizes transendothelial migration and chemotaxis of MonoMac6 cells and freshly isolated human monocytes induced by MCP-1, indicating a direct effect of s-FKN on monocytic cells. In this study, we found that stress-activated protein kinase (SAPK)1/c-Jun N-terminal kinase 1 and SAPK2/p38 are involved in the control of MCP-1-induced MonoMac6 cell migration. We demonstrated that s-FKN abrogates the MCP-1-induced SAPK2/p38 activation as well as the upstream Pyk2 activity. Furthermore, we observed that s-FKN also inhibits the activity of a major matrix metalloproteinase (MMP), namely MMP-2. Taken collectively, our results indicate that the s-FKN antagonizes the chemoattractant effect of MCP-1 on monocytes, likely by inhibiting crucial signaling pathways, like SAPK2/p38 and MMP-2 activities.

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“…These Rho-like G-proteins are known principally for their pivotal role in regulating the actin cytoskeleton in cell migration (Burridge and Wennerberg, 2004). PI3K has been thought to be a key molecule in the activation of cell migration through Rac signaling (Chandrasekar et al, 2003;van Leeuwen et al, 2003 Kawauchi et al, 2003) and p38MAPK (Rousseau et al, 1997;Cara et al, 2001;Ishizuka et al, 2001;Kimura et al, 2003;Pichon et al, 2004), have also been reported to be involved in cell migration. Consistent with these reports, our results indicate that activation of PI3K is required for the induction of glioma cell migration as well as for the activation of p38MAPK and JNK in response to LPA.…”

Section: Discussionmentioning

confidence: 99%

Role of p38 mitogen-activated kinase and c-Jun terminal kinase in migration response to lysophosphatidic acid and sphingosine-1-phosphate in glioma cells

et al. 2005

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A potential role for 1-oleoyl-sn-glycero-3-phosphate or lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) in the regulation of malignant diseases has been widely considered. In this study, we found that in transformed astroglial cells, the expression profile of lysophospholipid receptor mRNA and the action modes of LPA and S1P on cell motility were changed: there was a change in the acquisition of the ability of LPA to stimulate cell migration and a change in the migratory response to S1P from stimulation through S1P 1 to inhibition through S1P 2 . LPA-induced cell migration was almost completely inhibited by either pertussis toxin, LPA 1 receptor antagonists including Ki16425 (3-(4-[4-([1-(2-chlorophenyl)ethoxy]carbonyl amino)-3-methyl-5-isoxazolyl] benzylsulfonyl)propanoic acid) or an inhibitor of phosphatidylinositol 3-kinase (PI3K) wortmannin. The LPA-induced action was also suppressed, although incompletely, by several specific inhibitors for intracellular signaling pathways including Rac1, Cdc42, p38 mitogen-activated protein kinase (p38MAPK) and c-Jun terminal kinase (JNK), but not extracellular signalregulated kinase. Nearly complete inhibition of migration response to LPA, however, required simultaneous inhibition of both the p38MAPK and JNK pathways. Inhibition of Rac1 suppressed JNK but not p38MAPK, while the activity of p38MAPK was abolished by a dominantnegative form of Cdc42. These findings suggest that, in glioma cells, the PI3K/Cdc42/p38MAPK and PI3K/ Rac1/JNK pathways are equally important for LPA 1 receptor-mediated migration.

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Role of p38 Mitogen-Activated Protein Kinase in Chemokine-Induced Emigration and Chemotaxis In Vivo

Cited by 115 publications

References 36 publications

Activation of p38 MAPK is a key step in tumor necrosis factor–mediated inflammatory bone destruction

Activation of p38 MAPK is a key step in tumor necrosis factor–mediated inflammatory bone destruction

Soluble Fractalkine Prevents Monocyte Chemoattractant Protein-1-Induced Monocyte Migration via Inhibition of Stress-Activated Protein Kinase 2/p38 and Matrix Metalloproteinase Activities

Role of p38 mitogen-activated kinase and c-Jun terminal kinase in migration response to lysophosphatidic acid and sphingosine-1-phosphate in glioma cells

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