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* Department of Pharmacology, University of Illinois, Chicago, IL 60612; and
Department of Microbiology and Immunology, Medical University of Ohio, Toledo, OH 43614
The acute-phase proteins, C-reactive protein and serum amyloid A (SAA), are biomarkers of infection and inflammation. However, their precise role in immunity and inflammation remains undefined. We report in this study a novel property of SAA in the differential induction of Th1-type immunomodulatory cytokines IL-12 and IL-23. In peripheral blood monocytes and the THP-1 monocytic cell line, SAA induces the expression of IL-12p40, a subunit shared by IL-12 and IL-23. SAA-stimulated expression of IL-12p40 was rapid (
4 h), sustainable (
20 h), potent (up to 3380 pg/ml/106 cells in 24 h), and insensitive to polymyxin B treatment. The SAA-stimulated IL-12p40 secretion required de novo protein synthesis and was accompanied by activation of the transcription factors NF-
B and C/EBP. Expression of IL-12p40 required activation of the p38 MAPK and PI3K. Interestingly, the SAA-induced IL-12p40 production was accompanied by a sustained expression of IL-23p19, but not IL-12p35, resulting in preferential secretion of IL-23, but not IL-12. These results identify SAA as an endogenous ligand that potentially activates the IL-23/IL-17 pathway and present a novel mechanism for regulation of inflammation and immunity by an acute-phase protein.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by National Institutes of Health Grant AI040176 and by a Biomedical Science Grant from Arthritis Foundation. R.H. is a recipient of a Scientist Development Grant from the American Heart Association.
2 Address correspondence and reprint requests to Dr. Richard D. Ye, Department of Pharmacology, University of Illinois, 835 South Wolcott Avenue, Chicago, IL 60612. E-mail address: yer{at}uic.edu
3 Abbreviations used in this paper: APP, acute-phase protein; CRP, C-reactive protein; Ct, threshold cycle; FPRL1, formyl peptide receptor-like 1; HDL, high density lipoprotein; SAA, serum amyloid A; STBS, suspension cell transfection buffer solution.
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