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Receptors1
* Department of Internal Medicine and
Department of Molecular Genetics and Microbiology, University of New Mexico, Albuquerque, NM 87131;
Experimental Toxicology Program, Lovelace Respiratory Research Institute, Albuquerque, NM 87108;
Department of Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands; and
¶ Department of Veterans Affairs Medical Center, Albuquerque, NM 87108
C-reactive protein (CRP) is a member of the pentraxin family of proteins and an acute phase reactant. CRP modulates the response to inflammatory stimuli including LPS and C5a. We recently demonstrated that CRP prevents and reverses proteinuria in accelerated nephrotoxic nephritis (NTN). NTN is a model of active inflammatory immune complex-mediated nephritis induced by injection of antiglomerular basement membrane. CRP treatment prevented the induction of NTN in C57BL/6 (B6) mice, increased survival, and reversed ongoing nephritis. Protection was associated with a decrease in IL-1
and chemokines in the kidney and peritoneal cells as measured by quantitative RT-PCR. However, IL-10–/– mice were not protected by CRP either when given before disease onset or when disease activity was maximal. Fc
RI–/– mice developed NTN, but were only transiently protected by CRP treatment. This transient protection was abrogated by cobra venom factor depletion of complement from FcRI–/– mice. However, complement depletion did not prevent CRP-mediated protection in B6 mice, and CRP was protective in C3–/– mice. The role of macrophages in the protection provided by CRP was tested by treating B6 mice with liposomes containing clodronate. Clodronate-containing liposomes deplete mice of splenic and hepatic macrophages for 5–7 days. Pretreatment of NTN mice with clodronate but not control liposomes completely prevented CRP-mediated protection. These studies suggest that CRP mediates protection from NTN through the induction of IL-10 and that macrophages are required. In addition, FcRI plays an important role but is not the sole mediator of CRP-mediated protection.
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 by the Department of Veterans Affairs and by National Institutes of Health Grant AI-28358.
2 Address correspondence and reprint requests to Dr. Terry W. Du Clos, Veterans Affairs Medical Center, Research Service 151, 1501 San Pedro Southeast, Albuquerque, NM 87108. E-mail address: tduclos{at}unm.edu
3 Abbreviations used in this paper: CRP, C-reactive protein; PAF, platelet-activating factor; IC, immune complex; NTN, nephrotoxic nephritis; GBM, glomerular basement membrane; BUN, blood urea nitrogen; qRT-PCR, quantitative RT-PCR; CVF, cobra venom factor; IVIG, intravenous Ig; ITP, immune thrombocytopenic purpura; DC, dendritic cell.
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