Therapeutic Lowering of C-Reactive Protein

Abstract

In the blood of healthy individuals C-reactive protein (CRP) is typically quite scarce, whereas its blood concentration can rise robustly and rapidly in response to tissue damage and inflammation associated with trauma and infectious and non-infectious diseases. Consequently, CRP plasma or serum levels are routinely monitored in inpatients to gauge the severity of their initial illness and injury and their subsequent response to therapy and return to health. Its clinical utility as a faithful barometer of inflammation notwithstanding, it is often wrongly concluded that the biological actions of CRP (whatever they may be) are manifested only when blood CRP is elevated. In fact over the last decades, studies done in humans and animals (e.g. human CRP transgenic and CRP knockout mice) have shown that CRP is an important mediator of biological activities even in the absence of significant blood elevation, i.e. even at baseline levels. In this review we briefly recap the history of CRP, including a description of its discovery, early clinical use, and biosynthesis at baseline and during the acute phase response. Next we overview evidence that we and others have generated using animal models of arthritis, neointimal hyperplasia, and acute kidney injury that baseline CRP exerts important biological effects. In closing we discuss the possibility that therapeutic lowering of baseline CRP might be a useful way to treat certain diseases, including cancer.

Keywords: antisense oligonucleotide; autoimmunity; cancer; cardiovascular; pentraxin.

Figure 1

C-reactive protein (CRP) is a pentamer with two distinct faces. (A) On the A face each CRP monomer displays an α-helical stretch of residues (fuchsia) adjacent to the C1q and FcR binding sites and on the opposite B face (B) each monomer displays residues that help coordinate two Ca²⁺ ions (green spheres) that assist with binding to ligands (phosphocholine shown in gray, red, and orange spheres). The image is a reproduction of structure 1B09 as reported by (35, 36) and was created using NGL (37) accessed on PDB (–40).

Figure 2

The human C-reactive protein (CRP) gene. (A) Downstream of CRP is the CRP pseudo-gene (CRPP1, lilac box), that is likely involved in cis-acting regulation of basal CRP expression. (B) The proximal promoter of CRP (light blue box) is typically mapped as the region ~300 nucleotides upstream of the transcription start site, including the TATA binding site at −29 to −26 (red ×). The short 5’ untranslated region (5’UTR; light gray box) precedes the coding sequence for the 18 amino acid-long leader peptide (dark gray box). Exon 1 encodes the first three amino acids of mature CRP (thin black vertical line) and is immediately followed by the intron. The remainder of CRP is encoded by exon 2 (black box). CRP has a long 3’UTR sequence (light gray box) with a poly(A) signal (♦). Each region is drawn approximately to scale. (C) The relative locations in the CRP promoter of binding elements for hepatic nuclear factor (HNF) 1α and HNF3 that contribute to regulation of constitutive expression of CRP (gray boxes) and for C/EBP (yellow boxes), NF-κB (black boxes), and STAT3 (blue box) that contribute to regulation of expression of CRP during the acute phase response. Note that C/EBP and NF-κB and the repressor OCT-1 (red box) utilize overlapping elements.