title: Differential regulation of lipopolysaccharide and Gram-positive bacteria induced cytokine and chemokine production in macrophages by Galpha(i) proteins.
abstract: Heterotrimeric G(i) proteins play a role in signalling activated by lipopolysaccharide (LPS), Staphylococcus aureus (SA) and group B streptococci (GBS), leading to production of inflammatory mediators. We hypothesized that genetic deletion of G(i) proteins would alter cytokine and chemokine production induced by LPS, SA and GBS stimulation. LPS-induced, heat-killed SA-induced and heat-killed GBS-induced cytokine and chemokine production in peritoneal macrophages from wild-type (WT), Galpha(i2) (-/-) or Galpha(i1/3) (-/-) mice were investigated. LPS induced production of tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), IL-10 and interferon-gamma-inducible protein-10 (IP-10); SA induced TNF-alpha, and IL-1beta production; and GBS induced TNF-alpha, IL-6, IL-1beta, macrophage inflammatory protein-1alpha (MIP-1alpha) and keratinocyte chemoattract (KC) production were all decreased (P < 0.05) in Galpha(i2) (-/-) or Galpha(i1/3) (-/-) mice compared with WT mice. In contrast to the role of G(i) proteins as a positive regulator of mediators, LPS-induced production of MIP-1alpha and granulocyte-macrophage colony-stimulating factor (GM-CSF) were increased in macrophages from Galpha(i1/3) (-/-) mice, and SA-induced MIP-1alpha production was increased in both groups of Galpha(i) protein-depleted mice. LPS-induced production of KC and IL-1beta, SA-induced production of GM-CSF, KC and IP-10, and GBS-induced production of IL-10, GM-CSF and IP-10 were unchanged in macrophages from Galpha(i2) (-/-) or Galpha(i1/3) (-/-) mice compared with WT mice. These data suggest that G(i2) and G(i1/3) proteins are both involved and differentially regulate murine inflammatory cytokine and chemokine production in response to both LPS and Gram-positive microbial stimuli.
authors.affiliation: Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Hongkuan
authors.initials: H
authors.lastname: Fan
authors.forename: David L
authors.initials: DL
authors.lastname: Williams
authors.forename: Basilia
authors.initials: B
authors.lastname: Zingarelli
authors.forename: Kevin F
authors.initials: KF
authors.lastname: Breuel
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Teti
authors.forename: George E
authors.initials: GE
authors.lastname: Tempel
authors.forename: Karsten
authors.initials: K
authors.lastname: Spicher
authors.forename: Guylain
authors.initials: G
authors.lastname: Boulay
authors.forename: Lutz
authors.initials: L
authors.lastname: Birnbaumer
authors.forename: Perry V
authors.initials: PV
authors.lastname: Halushka
authors.forename: James A
authors.initials: JA
authors.lastname: Cook
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018925:Chemokines / Q000096:biosynthesis*; D016207:Cytokines / Q000096:biosynthesis; D044385:GTP-Binding Protein alpha Subunits / Q000276:immunology; D005838:Genotype; D008070:Lipopolysaccharides / Q000276:immunology*; D017737:Macrophages, Peritoneal / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D013211:Staphylococcus aureus / Q000276:immunology*; D013292:Streptococcus agalactiae / Q000276:immunology*
chemical_list: D018925:Chemokines; D016207:Cytokines; D044385:GTP-Binding Protein alpha Subunits; D008070:Lipopolysaccharides