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  • Title: p38 Mitogen-activated protein kinase up-regulates LPS-induced NF-kappaB activation in the development of lung injury and RAW 264.7 macrophages.
    Author: Kim HJ, Lee HS, Chong YH, Kang JL.
    Journal: Toxicology; 2006 Aug 01; 225(1):36-47. PubMed ID: 16793190.
    Abstract:
    Clarification of the key regulatory steps that lead to nuclear factor-kappa B (NF-kappaB) under cellular and pathological conditions is very important. The action of p38 mitogen-activated protein kinase (MAPK) on the upstream of NF-kappaB activation remains controversial. To examine this issue using an in vivo lung injury model, SB203580, a p38 MAPK inhibitor was given intraorally 1h prior to lipopolysaccharide (LPS) treatment (intratracheally). The mice were sacrificed 4 h after LPS treatment. SB203580 substantially suppressed LPS-induced rises in p38 MAPK phosphorylation, neutrophil recruitment, total protein content in bronchoalveolar lavage fluid, and apoptosis of bronchoalveolar cells. Furthermore, SB203580 blocked LPS-induced NF-kappaB activation in lung tissue through down-regulation of serine phosphorylation, degradation of IkappaB-alpha, and consequent translocation of the p65 subunit of NF-kappaB to the nucleus. It is likely that, in cultured RAW 264.7 macrophages, SB203580 also blocked LPS-induced NF-kappaB activation in a dose-dependent manner. SB203580 inhibited LPS-induced serine phosphorylation, degradation of IkappaB-alpha, and tyrosine phosphorylation of p65 NF-kappaB. These data indicate that p38 MAPK acts upstream of LPS-induced NF-kappaB activation by modulating the phosphorylation of IkappaB-alpha and p65 NF-kappaB during acute lung injury. Because LPS-stimulated macrophages may contribute to inflammatory lung injury, the inhibition of the p38 MAPK-mediated intracellular signaling pathway leading to NF-kappaB activation represents a target for the attenuation of lung inflammation and parenchymal damage.
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