title: Differential effects of p38- and extracellular signal-regulated kinase mitogen-activated protein kinase inhibitors on inducible nitric oxide synthase and tumor necrosis factor production in murine macrophages stimulated with Streptococcus pneumoniae.
abstract: The role of p38- and extracellular signal-regulated kinase (ERK) mitogen-activated protein (MAP) kinase pathways in the up-regulation of inducible nitric oxide synthase (iNOS) and tumor necrosis factor (TNF) production in macrophages stimulated with Streptococcus pneumoniae was examined. Inhibitors of p38 kinases effected significant decreases in the accumulation of iNOS protein in macrophages challenged with pneumococcal cell wall preparations or antibiotic-killed pneumococci, even when added up to 6 h after bacterial challenge. In contrast, ERK pathway inhibitors failed to inhibit pneumococcus-induced iNOS protein accumulation. ERK pathway inhibitors significantly reduced TNF secretion when added at the same time as pneumococcal challenge, and inhibitors of both ERK and p38 pathways reduced TNF secretion when added to the macrophages 1 h before stimulation. These data confirm the importance of the p38 and ERK MAP kinase pathways in macrophage activation by bacterial products but indicate that these 2 kinase pathways regulate different macrophage responses in a temporally distinct manner.
authors.affiliation: Children's Foundation Research Center at Le Bonheur Children's Medical Center and Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee 38103, USA.
authors.forename: Richelle M
authors.initials: RM
authors.lastname: Monier
authors.forename: Karen L
authors.initials: KL
authors.lastname: Orman
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Meals
authors.forename: B Keith
authors.initials: BK
authors.lastname: English
mesh_terms: D000818:Animals; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D013296:Streptococcus pneumoniae / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D004791:Enzyme Inhibitors; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases