Where is crp made

Among multiple inflammatory biomarkers, CRP boasts the largest body of research supporting its role as an independent risk factor in the development of CVD [ 15 — 19 ], as it actively participates in atherogenesis by directly influencing processes such as activation of the complement system, apoptosis, vascular cell activation, monocyte recruitment, lipid accumulation, and thrombosis. Both isoforms are involved in such processes: pCRP can generate inflammatory responses binding to the phosphatidylcholine on the exterior of LDL-ox and the surface of apoptotic cells [ 53 ], while mCRP is able to modulate platelet function inducing aggregation and contributes to atherothrombotic complications by promoting thrombosis [ 60 ] Figure 2.

The complement system is a set of enzymes and bioregulators with multiple biological activities, playing a key role in both innate alternative and lectin pathway and acquired classical pathway immunity. Its proper activation is essential for defense against pathogens and elimination of apoptotic and necrotic cells. Nevertheless, excessive or inappropriate activation of this system contributes to the pathogenesis of many chronic inflammatory diseases, including atherosclerosis [ 72 ].

Both CRP isoforms have the ability to interact with C1q, activating the classical pathway [ 73 , 74 ]. Recent studies report the presence of CRP mRNA and depots with high concentrations of C1q, C3, and C4 in atherosclerotic plaques [ 75 ], suggesting that CRP may amplify and facilitate activation of the classical pathway, with the subsequent formation of the membrane attack complex MAC. Furthermore, activation of this pathway may contribute to the establishment and progression of atherosclerosis by inducing the proliferation of arterial smooth muscle cells and increased synthesis and secretion of IL-8 and monocyte chemotactic protein MCP CRP also exhibits affinity with members of the factor H protein family, providing binding sites for factor H in the mCRP isoform, to which it binds in a calcium-independent fashion [ 77 ].

These proteins may facilitate recruitment of CRP to the surface of necrotic cells, acting as soluble regulators of the alternative pathway of the complement system [ 78 ]. Excessive activity of this pathway leads to the presence of high circulating levels of C3a and C5a, potent anaphylatoxins involved in local inflammatory responses [ 79 ]. In vitro studies have shown expression of CR3 and CR5a in coronary artery atherosclerotic plaques, favoring chemotaxis of monocytes, mast cells, and lymphocytes, expression of endothelial adhesion molecules, release of TNF and IL-1, and production of reactive oxygen species by macrophages located within the lesion [ 80 , 81 ].

Generally, this cascade would start with the sequential activation of a tyrosine protein kinase PKT of the Src family, which phosphorylates tyrosine residues of this motif, followed by activation of Syk tyrosine kinase [ 83 ]. This would result in the recruitment of multiple signaling molecules, including other kinases such as protein kinase C PKC , extracellular signal-regulating kinases ERK , mitogen activating protein kinases MAPK [ 84 ], and phosphatidyl inositolkinase PI3K , as well as phospholipase C PLC [ 85 ], intracellular adaptation molecules, and second messengers such as calcium Ca , diacylglycerol DAG , and inositolphosphate PI3 [ 85 , 86 ].

Recent reports suggest that pCRP may be a direct regulator of endothelial cell activation and dysfunction, by inducing the expression of intracellular adhesion molecules, vascular E-selectin, and monocyte chemoattractant protein-1 MCP-1 [ 88 ], which permits chemotaxis and binding of monocytes to endothelial cells during the early stages of atherogenesis [ 89 ].

Furthermore, CRP isoforms play an important differential role in the modulation of endothelial progenitor cell EPC proliferation. While pCRP appears to favor EPC proliferation and induce primarily noninflammatory gene expression of these cells, mCRP does not seem to affect EPC proliferation rate but rather induce upregulation of proinflammatory, interferon-responsive genes [ 93 ].

Metalloproteinases are proteolytic enzymes responsible for remodeling the extracellular matrix ECM , which have been implicated in the development and rupture of atherosclerotic plaques.

Nitric oxide NO is a simple gas produced by a group of enzymes termed NO synthases. These are widely distributed in several tissues, particularly in endothelial cells, where they mediate vasodilation and antioxidant and antithrombotic effects [ 99 ].

In vitro and in vivo studies indicate that CRP may interfere with NO synthesis by inhibiting endothelial nitric oxide synthase eNOS activity through various pathways, all of which ultimately lead to endothelial dysfunction [ ]. To this end, CRP has been demonstrated to inhibit GTP cyclohydrolase 1 through the p38 kinase pathway [ ]; this enzyme is the first step in the de novo synthesis of tetrahydrobiopterin, an important cofactor for eNOS.

As a result, decreased tetrahydrobiopterin leads to decoupling of eNOS and depletion of NO levels, favoring endothelial dysfunction. Yet another mechanism contributing to endothelial dysfunction involves modification of protein-protein interactions of eNOS with heat shock protein 90 Hsp90 and caveolin-1, decreasing binding to the former and increasing binding to the latter, resulting in reduced eNOS activity [ ].

Microenvironmental pH at the inflammation site plays a key role in the binding of CRP to lipoproteins, as the binding site for LDL-ox is only revealed after modifications in the structure of CRP triggered by acidic milieus [ , ]. Furthermore, despite being able to bind E-LDL at physiological pH, acidic pH enhances affinity for this modified lipoprotein [ 51 ]. This association is thought to lead to opsonization and subsequent phagocytosis of LDL-ox and, in consequence, formation of a characteristic component of atherosclerotic plaques: foam cells [ ] Figure 3.

In vivo assays have demonstrated that CRP not only promotes uptake of LDL-ox but also stimulates accumulation of cholesterol esters in human macrophages [ ]. Lastly, although pCRP may exert some anti-inflammatory effects by binding mmLDL and consequently attenuating monocyte activation, this property is lost when dissociated into mCRP, further highlighting the importance of this dissociation as a localized inflammation mechanism [ , ].

Each isoform appears to play distinct roles throughout the atherosclerotic process, and both are subjects of continuous study. In this context, the only relation between pCRP and activated platelets seems to be its dissociation into mCRP on their surface, as only the latter favors thrombosis in this scenario by promoting platelet aggregation, surface P-selectin and CD63 exposure, and glycoprotein IIb-IIIa activation [ ].

Likewise, mCRP induces expression of tissue factor in endothelial cells, favoring fibrinolytic resistance and endothelial dysfunction [ ], and is also much more effective than pCRP at inducing chemotaxis and binding to integrin in macrophages, as well [ ]. Indeed, current knowledge depicts mCRP to exhibit more deleterious actions than pCRP and seems to be more powerful regarding the effects they share in atherosclerosis [ 38 ], although further research may reveal novel aspects in the properties of both isoforms that may modify this outlook.

The concept of atherosclerosis has long diverged from mere lipid deposition in arterial walls, towards the current notion that describes it as a complex chronic inflammatory process. In this scenario, CRP may play an active role through a wide array of mechanisms, although primarily via activation of the complement system and metalloproteinases, and recruitment and activation of inflammatory cells. Simultaneously, CRP favors the establishment of a generalized chronic inflammatory state and in turn potentiating atherosclerosis.

Although mCRP appears to drive most of these effects, further research is required in order to differentially characterize the roles of CRP isoforms. Moreover, many epidemiological studies have shown an association between CRP and cardiovascular risk [ ], and its clinical utility is currently a topic of great debate, with novel proposals for scenarios where its evaluation may be useful, including the use of fractions of CRP as a new element in the diagnostic workup of patients with acute coronary syndrome [ ] and the designation of CRP as a potential therapeutic target given its exhaustive involvement in the pathophysiology of atherosclerosis [ ].

Thus, further experimental testing is required to elucidate its true involvement as a risk factor, as well as population studies exploring the epidemiologic behavior of CRP. This work was supported by research Grant no. FZ from Fundacite-Zulia. This is an open access article distributed under the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Article of the Year Award: Outstanding research contributions of , as selected by our Chief Editors. Read the winning articles. Academic Editor: Jose Antonio F. Received 31 Aug Accepted 01 Nov Published 16 Dec Abstract Cardiovascular disease is the leading cause of morbidity and mortality in the adult population worldwide, with atherosclerosis being its key pathophysiologic component.

Overview of C-Reactive Protein Structure and Metabolism CRP was first described in by Tillet and Francis, named after its ability to precipitate and interact with phosphorylcholine residues of the C polysaccharide derived from teichoic acid within the cellular wall of Streptococcus pneumoniae , as well as its ability to precipitate with calcium ions [ 12 ].

Figure 1. Molecular structure of C-reactive protein CRP. These are necessary for ligand binding. Table 1. Receptors, ligands, and function of C-reactive protein according to location. Figure 2.

Key participations of C-reactive protein in atherosclerosis. Figure 3. Role of C-reactive protein in the arterial intima during atherosclerosis. C-reactive protein is a cardiovascular risk factor that plays an important role in atherosclerotic events, found in unstable plaques in the vascular endothelium, along with other proatherogenic components. Binding of pCRP to activated platelets results in generation of mCRP, which can then enhance platelet adhesion to endothelial cells and stimulate formation of neutrophil-platelet aggregates, favoring thrombogenesis see text for further details.

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The role of inflammation in cancer is not well understood. Some organs of the body show greater risk of cancer when they are chronically inflamed. In a prospective cohort study on colon cancer risk associated with CRP levels, people with colon cancer had higher average CRP concentrations than people without colon cancer.

However, these findings may suggest that low inflammation level can be associated with a lower risk of colon cancer, concurring with previous studies that indicate anti-inflammatory drugs could lower colon cancer risk. It has previously been speculated that single-nucleotide polymorphisms in the CRP gene may affect clinical decision-making based on CRP in rheumatoid arthritis, e. File:Blood values sorted by mass and molar concentration. PMID The Journal of Clinical Investigation. PMC American Journal of Physiology.

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April The New England Journal of Medicine. November American Heart Journal. Annals of Internal Medicine. Archived from the original on Increased serum CRP is related to traditional cardiovascular risk factors and may reflect the role of these risk factors in causing vascular inflammation. According to the American Heart Association, results of the hs-CRP in determining the risk for heart disease can be interpreted as follows:.

Note: Normal value ranges may vary slightly among different laboratories. Talk to your health care provider about the meaning of your specific test results. The examples above show the common measurements for results for these tests. Some laboratories use different measurements or may test different specimens. A positive test means you have inflammation in the body. This may be due to a variety of conditions, including:. Note: Positive CRP results also occur during the last half of pregnancy or with the use of birth control pills oral contraceptives.

Risks associated with having blood drawn are slight, but may include:. Laboratory Tests and Diagnostic Procedures. Dietzen DJ. Amino acids, peptides, and proteins. In: Rifai N, ed. St Louis, MO: Elsevier; chap Risk markers and the primary prevention of cardiovascular disease. Philadelphia, PA: Elsevier; chap The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition.

A licensed physician should be consulted for diagnosis and treatment of any and all medical conditions.