Published online before print February 5, 2008

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0407203

Received for publication April 3, 2007.
Revised November 8, 2007.
Accepted for publication November 20, 2007.

Article

Is serum amyloid A an endogenous TLR4 agonist?

Silvana Sandri ^*, Dunia Rodriguez , Eliane Gomes , Hugo Pequeno Monteiro , Momtchilo Russo ^@, and Ana Campa ^*

Departments of *Clinical Analysis and Toxicology, Faculty of Pharmaceutical Sciences, and Immunology, Biomedical Science Institute, University of São Paulo, Brazil; and Department of Biochemistry/Molecular Biology/CINTERGEN, São Paulo, Brazil

^@ To whom correspondence should be addressed. E-mail: momrusso{at}icb.usp.br.

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.

Key Words: Toll like receptors • macrophages • nitric oxide (NO)

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