title: Complement regulates TLR4-mediated inflammatory responses during intestinal ischemia reperfusion.
abstract: Innate immune responses including TLR4 and complement activation are required for mesenteric ischemia/reperfusion (IR)-induced tissue damage. We examined the regulation of TLR4 and complement activation in a mouse model of intestinal IR. Intestinal IR-induced C3 deposition in a TLR4 dependent manner. In addition, in wild-type but not TLR4 deficient mice, IR significantly increased C3 and Factor B (FB) mRNA expression within the intestine. To further examine the role of TLR4 and complement, we administered the complement inhibitor, CR2-Crry, to target local complement activation in wild-type C57Bl/10, and TLR4 deficient B10/ScN mice. TLR4 deficient mice sustained less damage and inflammation after IR than wild-type mice, but administration of CR2-Crry did not further reduce tissue damage. In contrast, CR2-Crry treatment of wild-type mice was accompanied by a reduction in complement activation and in C3 and FB transcription in response to IR. CR2-Crry also significantly decreased intestinal IL-6 and IL-12p40 production in both the wild-type and TLR4 deficient mice. These data indicate that TLR4 regulates extrahepatic complement production while complement regulates TLR4-mediated cytokine production during intestinal IR.
authors.affiliation: Division of Biology, Kansas State University, Manhattan, KS 66506, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Pope
authors.forename: Sara M
authors.initials: SM
authors.lastname: Hoffman
authors.forename: Stephen
authors.initials: S
authors.lastname: Tomlinson
authors.forename: Sherry D
authors.initials: SD
authors.lastname: Fleming
mesh_terms: D000818:Animals; D003167:Complement Activation / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000276:immunology* / Q000293:injuries; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D015427:Reperfusion Injury / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051197:Toll-Like Receptor 4 / Q000276:immunology* / Q000378:metabolism
chemical_list: C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4
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