title: C5a controls TLR-induced IL-10 and IL-12 production independent of phosphoinositide 3-kinase.
abstract: The complement system is a classic central player in innate immunity. Most pathogens activate both complement and the toll-like receptor (TLR) pathway. Therefore, to provide a more comprehensive understanding of innate immunity, it is important to understand the crosstalk between these two systems. Mouse macrophages produce IL-12 and IL-10 in response to TLR ligands such as LPS, CpG, Poly I:C and Malp2. The TLR-induced IL-12 production was decreased, while that of IL-10 was increased by concurrent stimulation with a complement fragment C5a. Pharmacological studies have suggested that C5a regulates TLR4-induced IL-12 production in a phosphoinositide 3-kinase (PI3K)-dependent mechanism. In the present study, however, we found that the C5a-mediated changes can be observed in macrophages from mice lacking PI3K p85α or PI3K p110γ. The result indicates that the C5a action is PI3K-independent; neither class IA nor class IB PI3K subtype is involved in this regulation. The actions of C5a were sensitive to pertussis toxin and PD98059, suggesting a role of G protein-mediated activation of the Erk1/2 pathway.
authors.affiliation: Division of Molecular Medical Science, Graduate School of Biomedical Sciences, Hiroshima University, Minami-ku, Hiroshima, Japan.
authors.forename: Natsumi
authors.initials: N
authors.lastname: Okazaki
authors.forename: Kaoru
authors.initials: K
authors.lastname: Hazeki
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Izumi
authors.forename: Kiyomi
authors.initials: K
authors.lastname: Nigorikawa
authors.forename: Osamu
authors.initials: O
authors.lastname: Hazeki
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D016753:Interleukin-10 / Q000378:metabolism*; D018664:Interleukin-12 / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D037342:Pertussis Toxin / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012697:Serine Endopeptidases / Q000494:pharmacology*; D051193:Toll-Like Receptors / Q000378:metabolism*; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D005419:Flavonoids; D016753:Interleukin-10; D018664:Interleukin-12; D008070:Lipopolysaccharides; D037342:Pertussis Toxin; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012697:Serine Endopeptidases; D051193:Toll-Like Receptors; D000077191:Wortmannin; C041833:complement C5a-inhibitors; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one