Edited by Luke O'NeillC-reactive protein (CRP) is present at sites of inflammation including amyloid plaques, atherosclerotic lesions, and arthritic joints. CRP, in its native pentameric structural conformation, binds to cells and molecules that have exposed phosphocholine (PCh) groups. CRP, in its non-native pentameric structural conformation, binds to a variety of deposited, denatured, and aggregated proteins, in addition to binding to PCh-containing substances. In this study, we investigated the effects of H 2 O 2 , a prototypical reactive oxygen species that is also present at sites of inflammation, on the ligand recognition function of CRP. is a biological modifier of the structure and ligand recognition function of CRP. Overall, the data suggest that the ligand recognition function of CRP is dependent on the presence of an inflammatory microenvironment. We hypothesize that one of the functions of CRP at sites of inflammation is to sense the inflammatory microenvironment, change its own structure in response but remain pentameric, and then bind to pathogenic proteins deposited at those sites. C-reactive protein (CRP)3 is a pentameric molecule made up of five non-covalently associated, identical subunits arranged symmetrically around a central pore (1, 2). The ligand recognition function of native pentameric CRP is to bind, in a Ca 2ϩ -dependent manner, to phosphocholine (PCh)-containing substances, such as pneumococcal cell wall C-polysaccharide (PnC), necrotic cells, platelet-activating factor, PCh-containing molecules on the surface of parasites, enzymatically modified LDL, and oxidized LDL (ox-LDL) if the oxidation was sufficient to expose the PCh groups present in LDL (3-10). Under certain conditions, such as in an acidic pH buffer, CRP adapts a different pentameric configuration that exposes a hidden ligandbinding site for non-PCh ligands and that enables CRP to bind to immobilized, denatured, and aggregated proteins, irrespective of the identity of the native protein (11)(12)(13) , respectively, also converts CRP into molecules that bind to a variety of immobilized, denatured, and aggregated proteins (11,14).CRP is a plasma protein that is present at sites of inflammation such as necrotic areas in local inflammatory lesions, synovium of patients with rheumatoid arthritis, inflammatory lesions of experimental allergic encephalomyelitis, inflammatory and arterial atherosclerotic lesions, and neurofibrillary tangles of Alzheimer's disease (15)(16)(17)(18)(19)(20)(21)(22). When CRP is present at sites of inflammation, it is exposed to an inflammatory microenvironment. The microenvironment at sites of inflammation including arterial lesions in atherosclerosis, inflammation in the eye and the sites of bacterial infection, is characterized by acidic pH, hypoxia, and increased O 2 and energy demand, which result in the production of reactive oxygen species (ROS), including H 2 O 2 , and subsequent dysregulation of the extracellular redox environment, which is known to cause modifications in the proteins prese...

Background:The functions of C-reactive protein (CRP) in the extracellular matrix at the sites of inflammation are unknown. Results: Mutation of just one amino acid in CRP (E42Q) expands its ligand-binding capacity. Conclusion: Some functions of CRP depend upon its inflammation-induced structural configuration. Significance: Investigations using E42Q-CRP in animal models of inflammatory diseases may establish its therapeutic potential, the functions of CRP, and a CRP-targeting strategy.

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C-reactive protein (CRP), a plasma protein of the innate immune system, is produced by hepatocytes. A critical regulatory region (−42 to −57) on the CRP promoter contains binding site for the IL-6-activated transcription factor C/EBPβ. The IL-1β-activated transcription factor NF-κB binds to a κB site located nearby (−63 to −74). The κB site overlaps an octamer motif (−59 to −66) which is the binding site for the constitutively active transcription factor Oct-1. Oct-1 is known to function both as a transcriptional repressor and as an activator depending upon the promoter context. Also, Oct-1 can regulate gene expression either by binding directly to the promoter or by interacting with other transcription factors bound to the promoter. The aim of this study was to investigate the functions of Oct-1 in regulating CRP expression. In luciferase transactivation assays, overexpressed Oct-1 inhibited (IL-6+IL-1β)-induced CRP expression in Hep3B cells. Deletion of the Oct-1 site from the promoter drastically reduced the cytokine response because the κB site was altered as a consequence of deleting the Oct-1 site. Surprisingly, overexpressed Oct-1 inhibited the residual (IL-6+IL-1β)-induced CRP expression through the promoter lacking the Oct-1 site. Similarly, deletion of the Oct-1 site reduced the induction of CRP expression in response to overexpressed C/EBPβ, and overexpressed Oct-1 inhibited C/EBPβ-induced CRP expression through the promoter lacking the Oct-1 site. We conclude that Oct-1 acts as a transcriptional repressor of CRP expression and it does so by occupying its cognate site on the promoter and also via other transcription factors by an as yet undefined mechanism.

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