Interleukin-17 Stimulates C-reactive Protein Expression in Hepatocytes and Smooth Muscle Cells via p38 MAPK and ERK1/2-dependent NF-κB and C/EBPβ Activation

Abstract

C-reactive protein (CRP)2 is an acute phase reactant that is markedly increased during infection, inflammation, and tissue injury (1-5). It is synthesized and secreted mainly by the liver in response to circulating inflammatory mediators (6, 7). Elevated serum CRP levels serve as a risk marker for cardiovascular disease and predict future cardiovascular events and mortality (8, 9).Data obtained both in vivo and in vitro indicate that CRP plays a role in vascular inflammation (10 -12). CRP can be detected in human atherosclerotic plaques co-localized with modified low density lipoprotein (13,14). It can also associate with the terminal complex of complement in the arterial wall, inducing its activation in plaques. CRP promotes the uptake of low density lipoprotein by macrophages (15) and exerts a mitogenic effect on vascular smooth muscle cells (16). CRP stimulates chemokine and adhesion molecule expression in vascular endothelial cells and enhances platelet adhesion to endothelial cells (17). These data suggest that CRP is not just a marker of cardiovascular risk but is a risk factor in its own right, and CRP plays a causal role in atherosclerosis and thrombosis. In fact, transgenic overexpression of human CRP has been shown to promote atherosclerosis in apoE Ϫ/Ϫ mice (18), as does chronic administration (19). These data support an hypothesis that CRP is a proinflammatory and pro-atherogenic factor.Inflammation is an important component in all stages of atherosclerosis, with proinflammatory cytokines and chemokines playing critical roles. IL-17 is a member of a novel group of proinflammatory cytokines that is composed of six major isoforms, IL-17A, -B, -C, -D, -E (also known as IL-25), and -F (20). These isoforms are encoded by unique genes and share little homology with other interleukins. IL-17 signals via IL-17 receptors, products of unique genes, and includes IL-17RA, -B (also known as IL-25R), -C, -D, and -E (20).IL-17A is the most widely studied cytokine of the IL-17 family. It signals via IL-17RA and exerts proinflammatory, pro-apoptotic, and pro-mitogenic effects. Unlike IL-17, which is considered a T-cell-specific cytokine (21), many cell types in the body express the receptors and are therefore targets of . In this study we investigated whether IL-17 stimulates CRP expression in human hepatocytes and CASMC, and we determined the signal transduction pathways involved in * This work was supported in part by the Research Service of the Department of Veterans Affairs and NHLBI Grant HL68020 from the National Institutes of Health (to B. C.). 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 To whom correspondence should be addressed: Medicine/Cardiology,

Substance P enhances NF-κB transactivation and chemokine response in murine macrophages via ERK1/2 and p38 MAPK signaling pathways

“…The role of ERK1/2 and p38 MAPK in regulating NF-B activity varies in a stimulus-and cell type-specific manner. The finding that ERK1/2 control NF-B-dependent gene expression without affecting DNA binding has been supported by earlier studies (1,12,31,39,43). Our demonstration that SP induces Ser 276 phosphorylation of NF-B p65 and its nuclear translocation represents one mechanism for SP-elicited NF-B activation and chemokine induction in macrophages.…”

C-reactive protein levels in hereditary angioedema

“…Interestingly, IL-17 was also elevated in the absence of symptoms [30]. This cytokine stimulates CRP expression in hepatocytes and smooth muscle cells [31]. Therefore, the presence of IL-17 during asymptomatic periods could be a possible explanation for CRP increase.…”

Regulated conformation changes in C-reactive protein orchestrate its role in atherogenesis

“…CRP produced by the liver appears to primarily serve as a systemic inflammation marker with some antiinflammatory activities [53]. In inflammatory loci, CRP molecules either synthesized by local extra-hepatic cells [95][96][97][98][99] or entered into these loci from circulation can dissociate into mCRP with the aid of damaged cell membranes and acidic stresses. mCRP may mainly act as a pattern recognition molecule to facilitate the mobilization of the innate immunity and the clearance of damaged materials.…”