p38 mitogen-activated protein kinase up-regulates LPS-induced NF-κB activation in the development of lung injury and RAW 264.7 macrophages

Clarification of the key regulatory steps that lead to nuclear factor-kappa B (NF-kappa B) under cellular and pathological conditions is very important. The action of p38 mitogen-activated protein kinase (MAPK) on the upstream of NF-kappa B activation remains controversial. To examine this issue using an in vivo lung injury model, SB203580, a p38 MAPK inhibitor was given intraorally 1 h 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-kappa B activation in lung tissue through down-regulation of serine phosphorylation, degradation of I kappa B-alpha, and consequent translocation of the p65 subunit of NF-kappa B to the nucleus. It is likely that, in cultured RAW 264.7 macrophages, SB203580 also blocked LPS-induced NF-kappa B activation in a dose-dependent manner. SB203580 inhibited LPS-induced serine phosphorylation, degradation of I kappa B-alpha, and tyrosine phosphorylation of p65 NF-kappa B. These data indicate that p38 MAPK acts upstream of LPS-induced NF-kappa B activation by modulating the phosphorylation of I kappa B-alpha and p65 NF-kappa B 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-kappa B activation represents a target for the attenuation of lung inflammation and parenchymal damage. (c) 2006 Elsevier Ireland Ltd. All rights reserved.