An Intracellular Signaling Pathway Linking Lipopolysaccharide Stimulation to Cellular Responses of the Human Neutrophil: The p38 MAP Kinase Cascade and its Functional Significance

Abstract

Activation and accumulation of neutrophils in the lung by proinflammatory stimuli is a central event in the pathogenesis of ARDS. Following exposure of the neutrophil to a stimulus, sequential phosphorylation of kinases creates an intracellular signal that results in specific functional responses. Integral to many intracellular signaling pathways is activation of a three-part mitogen-activated protein (MAP) kinase cascade. MAP kinases (MAPk) are a highly conserved superfamily that are central to the regulation of cell growth, differentiation, and stress responses. 1 Cobb MH Goldsmith EJ How MAP kinases are regulated. J Biol Chem. 1995; 270: 14843-14846 Crossref PubMed Scopus (1659) Google Scholar At least three distinct families of MAPks exist in mammalian cells: the p42/44 extracellular signal-regulated kinase (ERK) MAPks, 2 Davis RJ The mitogen-activated protein kinase signal transduction pathway. J Biol Chem. 1993; 268: 14553-14556 Abstract Full Text PDF PubMed Google Scholar c-Jun NH2-terminal kinases, 3 Dérijard B Hibi M Wu I-H et al. JNK1: a protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain. Cell. 1994; 76: 1025-1037 Abstract Full Text PDF PubMed Scopus (2953) Google Scholar and the p38 MAPk. 4 Han J Lee J-D Bibbs L et al. A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science. 1994; 265: 808-811 Crossref PubMed Scopus (2407) Google Scholar Stimulation of human neutrophils with lipopolysaccharide (LPS) has been shown to result in the phosphorylation and activation of the p38 MAP kinase (MAPk), but not the p42/44 MAPks or the c-Jun NH2-terminal MAPk. 5 Nahas N Molski TFP Fernandez GA et al. Tyrosine phosphorylation and activation of a new mitogen-activated protein (MAP)-kinase cascade in human neutrophil stimulated with various agonists. Biochem J. 1996; 318: 247-253 Crossref PubMed Scopus (121) Google Scholar , 6 Nick JA Avdi NJ Gerwins P et al. Activation of a p38 mitogen-activated protein kinase in human neutrophils by lipopolysaccharide. J Immunol. 1996; 156: 4867-4875 PubMed Google Scholar , 7 Fouda BI Molski TFP Ashour MS et al. Effect of lipopolysaccharide on mitogen-activated protein kinases and cytosolic phospholipase A2. Biochem J. 1995; 308: 815-822 Crossref PubMed Scopus (51) Google Scholar The goal of this study is to expand our knowledge of the intracellular signaling pathway utilized by the neutrophil in response to LPS by addressing two fundamental questions: what upstream kinase activates p38 MAPk, and what are the functional consequences of this activation?