CRP (C-Reactive Protein) As An Accessory Signaling Molecule
CRP, as C-Reactive Protein is known, is an accessory signaling molecule. CRP modulates cell-cell interaction by transmission of activation signals and by stimulation of the release of cytokines and chemokines. By these effects, accessory signaling molecules may induce or propagate an inflammation. CRP plays a role in inflammation caused by conditions such as nephritis.
CRP And Inflammation
C-reactive protein (CRP) is an acute phase reactant that is characterized by a rapid and dramatic response to an inflammatory stimulus. CRP production is capable of increasing 1000-fold and is frequently elevated in autoimmune disorders, trauma, infection, and malignancy. High-sensitivity CRP, a means of detecting and quantifying variations in CRP when levels are below the limit of standard assays, has assumed an increasingly prominent role in the detection of vascular inflammation and prediction of cardiovascular risk.
There is evidence that CRP may participate in atherogenesis, with data to suggest its involvement in nearly every identified step. The production of proinflammatory cytokines in monocytes and macrophages is stimulated by CRP. CAM expression is enhanced by CRP, leading to increased leukocyte adhesion and migration. Increased CRP levels suppress vascular endothelial cell expression and activity of endothelial nitric oxide synthase. Decreased levels of endothelial nitric oxide synthase, leading to vascular endothelial dysfunction, are believed to be a key component of the initiation of atherogenesis. Furthermore, CRP promotes a procoagulant state. Increased levels of CRP induce plasminogen activator inhibitor-1 expression and activity in endothelial cells. In addition, red blood cell adhesiveness and aggregation increase with elevated CRP levels.
C-Reactive Protein Heightens Risk
C-reactive protein has been identified in atherosclerotic lesions, co-localized with complement. Multiple studies identify increased CRP levels as an independent risk factor for atherosclerotic vascular disease. Data from a study reveal that this association is less robust in healthy males when controlling for other markers of inflammation, such as fibrinogen and IL-6. However, in women CRP remains an independent risk factor after this adjustment. Data from another study suggests that CRP levels provide no additional predictive value for cardiovascular events in the elderly when other risk factors are accounted for.
Elevated CRP predicts cardiovascular morbidity and mortality in patients with CAD. In patients with acute myocardial infarction, levels of CRP are associated with plaque area and remodeling ratio. Left ventricular volume after MI correlates with increased peak CRP levels. C-reactive protein levels also predict long-term mortality after acute myocardial infarction, independent of infarct size.
CD40/CD40L : Another Accessory Signaling Molecule
CD40L is found on activated T cells and platelets and binds to its cognate receptor CD40, found primarily on endothelial cells and antigen-presenting cells. This interaction contributes to the inflammatory response by the upregulation of cellular expression of class II molecules and adhesion molecules, and through the secondary secretion of inflammatory cytokines including IL-1, TNF-a, IL-12, and inflammatory chemokines. A recent trial using an anti-CD40L antibody in treatment of proliferative lupus nephritis resulted in decreased hematuria and dsDNA antibodies, but was ended prematurely because of thromboembolic events.
The production of acute phase proteins is a normal physiologic response to cytokines released in both chronic and acute flammatory states. Although acute phase proteins, such as C-reactive protein, may provide protection against pathogens, they also can perpetuate or amplify inflammation with subsequent adverse effects.
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