How C-Reactive Protein Structural Isoforms With Distinctive Bioactivities Affect Disease Progression

Abstract

C-reactive protein (CRP) is a widely known, hepatically synthesized protein whose blood levels change rapidly and pronouncedly in response to any tissue damaging event associated with an inflammatory response. The synthesis and secretion of CRP is stimulated by interleukin-6, an early pleiotropic cytokine released by macrophages, endothelial, and other cells that are activated when localized normal tissue structures are compromised by trauma or disease. Serum CRP levels can change rapidly and robustly from 10-100-fold within 6-72 h of any tissue damaging event. Elevated blood levels correlate with the onset and extent of both activated inflammation and the acute phase biochemical response to the tissue insult. Because its functional bioactivity as the prototypic acute phase reactant has eluded clear definition for decades, diagnosticians of various conditions and diseases use CRP blood levels as a simple index for ongoing inflammation. In many pathologies, which involves many different tissues, stages of disease, treatments, and responses to treatments, its interpretive diagnostic value requires a deeper understanding of the localized tissue processes and events that contribute signals which regulate protective or pathological host defense bioactivities. This report presents concepts that describe how local tissue activation events can lead to a non-proteolytic, conformational rearrangement of CRP into a unique isoform with distinctive solubility, antigenicity, binding reactivities and bioactivities from that protein widely known and measured in serum. By describing factors that control the expression, tissue localization, half-life and pro-inflammatory amplification activity of this CRP isoform, a unifying explanation for the diagnostic significance of CRP measurement in disease is advanced.

C-Reactive Protein Triggers Cell Death in Ischemic Cells

“…Recent studies exceedingly revealed that CRP modulates signaling cascades besides the classical complement pathway (51)(52)(53)(54). This shows that CRP has direct physiological effects on not only inflammation but also the function of e.g., endothelial cells, be it their metabolism, differentiation or migration (55)(56)(57). In the context of endothelial cells, it is also discussed if CRP might have protective effects in atherosclerotic lesions.…”

C-Reactive Protein and Cancer: Interpreting the Differential Bioactivities of Its Pentameric and Monomeric, Modified Isoforms

“…Our group has published two recent reviews ( 6 , 7 ) that specifically address both the diagnostic interpretation of and the biological activities of pCRP, hsCRP and mCRP in cancer. Readers are directed to these reviews for details, developments, and cross references.…”

“…In this review, we describe previous studies of how “CRP” affected various acute phase and inflammation processes of relevance in cancer disease. By reinterpreting results to include concepts of mCRP, a more consistent understanding of how “CRP” contributes to the acute phase/inflammatory response in cancer, and in any disease involving tissue damage, is advanced ( 6 , 7 , 23 ).…”

“…Over the more recent decades, however, numerous studies have shown that CRP is, in fact, a protein that can undergo a non-proteolytic subunit dissociation which results in a conformational change into at least two structurally and functionally distinctive isoforms. When dissociated, the serum soluble diagnostically useful pentameric, non-glycosylated protein (referred to as “pentameric” or “pCRP”) is converted into an antigenically distinct isoform that has reduced aqueous solubility such that it can partition into cholesterol-rich membrane lipid rafts (referred to as “modified-monomeric” or “mCRP”) ( 5 , 7 ). Of underappreciated significance, mCRP can form from purified pCRP spontaneously with storage or by exposing pCRP to surfaces that contribute apolar binding sites ( 8 ).…”

Pronounced Diurnal Pattern of Salivary C-Reactive Protein (CRP) With Modest Associations to Circulating CRP Levels

“…The pentameric structure of CRP is dependent upon the presence of calcium, although it can also be disrupted irreversibly into monomers under denaturing conditions, such as an acidic local microenvironment. Monomeric/modified CRP can be deposited in tissues, but the biological relevance of this remains unclear and warrants further investigation ( 5 – 8 ).…”