A New Perspective on the Biology of C-Reactive Protein

C-reactive protein (CRP), composed of 5 23-kDa subunits, was traditionally viewed as one of the acute phase reactants.1 More recently, CRP has risen in statue to subsume the role of the "best" marker of inflammation useful in the prediction of future cardiovascular risks. 2 However, the clinical utility of CRP measurement in cardiovascular risk prediction is still not well defined.Furthermore, there is an intense debate on whether CRP is merely a marker of inflammation or a direct participant.1 The finding reported by Dr Janos Filep's group in this issue of Circulation Research provides additional insights into the current CRP debate.3 In this editorial, I will focus my discussion on 2 main issues.Where is CRP produced?And, is CRP biologically active?Where Is CRP Produced?CRP was traditionally thought to be produced by the liver in response to inflammatory cytokines.Several recent studies, however, clearly showed that CRP can be produced by nonhepatic tissues.Two studies have shown that both epithelial cells of the respiratory tract and renal epithelium can produce CRP under certain circumstances.4,5 Moreover, neuronal cells also seem to be capable of synthesizing acute phase reactants involved in the pathogenesis of neurodegenerative disease such as Alzheimer disease.6 These new sources of CRP production pointed to a more systemic generation of CRP in our body.However, these new sources provided only tenuous link to atherosclerosis.CRP has been shown to colocalize with the terminal complement complex in atherosclerotic plaques.7 Furthermore, Yasojima et al reported that mRNAs for CRP and the classical complement components C1 to C9 could be detected in both normal artery and plaque tissue.8 We recently showed that human coronary artery smooth muscle cells, but not human umbilical vein endothelial cells, could synthesize CRP after stimulation by inflammatory cytokines.9 This locally produced CRP may directly participate in the pathogenesis of atherosclerosis.Moreover, we have also shown that human adipocytes could produce CRP after stimulation by inflammatory cytokines and by a specific adipokine, resistin.10 Production of CRP by adipocytes may partially explain why CRP levels are elevated in patients with metabolic syndrome (Figure ).