title: Is serum amyloid A an endogenous TLR4 agonist?
abstract: Serum amyloid A (SAA), a classical acute-phase protein, is produced predominantly by hepatocytes in response to injury, infection, and inflammation. It has been shown that SAA primes leukocytes and induces the expression and release of proinflammatory cytokines. Here, we report that SAA induces NO production by murine peritoneal macrophages. Using specific inhibitors, we showed that NO production was dependent on inducible NO synthase thorough the activation of ERK1/2 and p38 MAPKs. Moreover, SAA activity was decreased after proteolysis but not with polymyxin B, a lipid A antagonist. Finally, we found that NO production was dependent on functional TLR4, a receptor complex associated with innate immunity. Macrophages from C3H/HeJ and C57BL/10ScCr mice lacking a functional TLR4 did not respond to SAA stimulation. In conclusion, our study makes a novel observation that SAA might be an endogenous agonist for the TLR4 complex on macrophages. The contribution of this finding in amplifying innate immunity during the inflammatory process is discussed.
authors.affiliation: Department of Clinical Analysis and Toxicology, Faculty of Pharmaceutical Sciences, Biomedical Science Institute, University of São Paulo, São Paulo, SP, Brazil.
authors.forename: Silvana
authors.initials: S
authors.lastname: Sandri
authors.forename: Dunia
authors.initials: D
authors.lastname: Rodriguez
authors.forename: Eliane
authors.initials: E
authors.lastname: Gomes
authors.forename: Hugo Pequeno
authors.initials: HP
authors.lastname: Monteiro
authors.forename: Momtchilo
authors.initials: M
authors.lastname: Russo
authors.forename: Ana
authors.initials: A
authors.lastname: Campa
mesh_terms: D000818:Animals; D003208:Concanavalin A / Q000494:pharmacology; D004731:Endotoxins / Q000633:toxicity; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D011112:Polymyxin B / Q000494:pharmacology; D000685:Serum Amyloid A Protein / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000819:agonists*
chemical_list: D004731:Endotoxins; D004791:Enzyme Inhibitors; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D000685:Serum Amyloid A Protein; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D003208:Concanavalin A; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D020929:Mitogen-Activated Protein Kinase Kinases; D011112:Polymyxin B