This Article Full Text (PDF) References Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Sommer, J.A. Articles by Proctor, R.A. Search for Related Content PubMed Articles by Sommer, J.A. Articles by Proctor, R.A. Social Bookmarking                         What's this?

Purinergic receptor modulation of LPS-stimulated signaling events and nitric oxide release in RAW 264.7 macrophages

Department of Biomolecular Chemistry, University of Wisconsin Medical School, Madison, Wisconsin, USA, Program in Molecular and Cellular Pharmacology, University of Wisconsin Medical School, Madison, Wisconsin, USA

P.L. Fisette

Department of Biomolecular Chemistry, University of Wisconsin Medical School, Madison, Wisconsin, USA, Program in Cell and Molecular Biology, University of Wisconsin Medical School, Madison, Wisconsin, USA

Y. Hu

Department of Biomolecular Chemistry, University of Wisconsin Medical School, Madison, Wisconsin, USA

L.C. Denlinger

Department of Biomolecular Chemistry, University of Wisconsin Medical School, Madison, Wisconsin, USA, Department of Medicine, University of Wisconsin Medical School, Madison, Wisconsin, USA

A.N. Guerra

Department of Biomolecular Chemistry, University of Wisconsin Medical School, Madison, Wisconsin, USA

P.J. Bertics

Department of Biomolecular Chemistry, University of Wisconsin Medical School, Madison, Wisconsin, USA, Program in Molecular and Cellular Pharmacology, University of Wisconsin Medical School, Madison, Wisconsin, USA, Program in Cell and Molecular Biology, University of Wisconsin Medical School, Madison, Wisconsin, USA

R.A. Proctor

Department of Medical Microbiology and Immunology, University of Wisconsin Medical School, Madison, Wisconsin, USA, Department of Medicine, University of Wisconsin Medical School, Madison, Wisconsin, USA

Purinergic receptors of the P2 class are cell surface receptors which are sensitive to extracellular adenine nucleotides, such as ATP and ADP. This class of receptors is divided into the P2Y family of G protein-coupled receptors and the P2X family of ligand-gated ion channels. The P2X receptors, seven of which have been cloned, are thought to possess two transmembrane domains and function as multimeric complexes. Numerous studies have suggested a role for P2 receptors in activation of macrophages by Gram-negative bacterial endotoxin (lipopolysaccharide; LPS). LPS is thought to exert its toxic effects, in large part, by inducing macrophages to release inflammatory mediators such as tumor necrosis factor (TNF), interleukin-1 (IL-1) and nitric oxide (NO). Although multiple signal transduction pathways are activated by LPS in macrophages, the proximal mechanisms by which LPS exerts these effects remain unclear. The current study examines the role of the P2X₇/P2Z purinergic receptor in LPS signaling events and in nitric oxide (NO) production. The results indicate that the P2X₇ receptor is required for maximal LPS activation of the mitogenactivated protein (MAP) kinases extracellular signal-regulated kinase (ERK)1 and ERK2, for activation of nuclear factor (NF)-B, as well as for upregulation of the inducible form of nitric oxide synthase (iNOS). These results are fortified by our recent observation that the C-terminus of the P2X₇ receptor is homologous to conserved LPS binding domains of proteins critical to host responses to Gram-negative bacterial infection, such as LPS-binding protein (LBP) and bactericidal permeability-increasing protein (BPI). Taken together, these observations suggest that the P2X ₇ receptor plays a fundamental role in LPS signal transduction and activation of macrophages, and thus may represent a therapeutic target for Gram-negative bacterial septicemia.

Journal of Endotoxin Research, Vol. 5, No. 1-2, 70-74 (1999)
DOI: 10.1177/09680519990050010501


CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?