Tillett and Francis (1930) noticed that C polysaccharide of Pneumococcus precipitated in the serum of patients with lobar pneumonia. During the acute stage of the disease, precipitation test was positive, while negative shortly after recovery. This indicated that there was a substance reactive only during the acute phase of the infectious disease which was confirmed in sera taken from children in acute phase of Gram-negative bacilli by Ash (1933). Abernethy and Francis (1937) injected C carbohydrate in patients with acute phase of pneumonia and noticed specific skin reactions associated with the effect of precipitation of C polysaccharide. Abernethy and Avery (1941) showed that serum taken from humans and monkeys contained protein that has the ability to precipitate with C polysaccharide during the acute stage of various infectious diseases, but in the presence of Ca2+. Later, C reactive protein (CRP) was described as native protein synthesized predominantly in liver.
Regulation of CRP Activity and Measurement
C reactive protein (CRP) belongs to a highly conserved protein family named pentraxins. It is encoded by CRP gene also named Pentraxin-Related, Pentraxin 1, and PTX1 gene. CRP gene is 1.9 kb long and contains one intron. It is located on chromosome 1q23.2. Pentraxin 1 protein, that is, CRP is involved in acute-phase response (inflammation, infection, neoplasia) in endothermic animals and humans (Pepys and Hirschfield 2003). CRP binds to the microbial polysaccharides and phosphatidylcholine in a calcium-dependent way. CRP activates the classical complement pathway C 1q, induces activity of phagocytes, and modulates activation of platelets (Westhuyzen and Healy 2000). Its structure is represented by symmetric pentamer that has five identical 24 kDa subunits containing 206 amino acids, each. Subunits are noncovalently connected. CRP is glycosylated in every species except in humans, rabbits, horses, and cows (Westhuyzen and Healy 2000) and is predominantly synthesized in hepatocytes. Hepatocytes in physiological conditions produce relatively low rates of CRP and store them in endoplasmic reticulum (ER) through the interaction with gp60a and gp60b carboxylesterases. Two carboxylesterases are retained in the ER by COOH-terminal retention signals (HIEL-COOH) and (HTEL-COOH). During the acute-phase response, CRP levels rise, while its affinity to bind gp60b decreases. Large amounts of CRP (up to 1000-fold) are released into the circulation from ER, as a response to inflammation (Yue et al. 1996). Interleukins IL-1, IL-6, and tumor necrosis factor (TNF) levels rise during the acute-phase response, as well. In human plasma, CRP half-life is nearly 19 h. About 70% of the CRP is detected in vascular compartment. CRP binds to the specific receptors on monocyte, macrophage, and neutrophil surfaces. It binds to phosphocholine with hydrophobic pocket positioned on the Phe-66 residue with cooperation of Lys-57, Arg-58, and Trp-67. Minimum length recognized by the CRP receptor contains 31–36 (KAFTVC) residues. It has been reported that functionally active sequence is represented by 33–37 (FTVCL) residues. Specific sequence is found in all of five subunits which represents a unique recognition motif for leukocytes related to inflammation (Westhuyzen and Healy 2000). In intact cells, chromatin and small ribonucleoproteins recognize and interact with CRP. Also, CRP binds to some other ligands, such as laminin, fibronection, and lipids (low-density and very-low density lypoproteins). Additive genetic factors account up to 40% of the variance of CRP levels in plasma according to the family and twin study reported by MacGregor et al. (2004).
For the infection screening, standard CRP assay is used. Immunoassay method is sensitive enough to quantify concentration of high-sensitivity CRP (hsCRP) from blood samples. hsCRP became one of the important biomarkers of CVD and metabolic syndrome. hsCRP levels greater than 1 mg/L indicate intermediate primary cardiovascular risk, while levels higher than 3 mg/L suggest high risk for CVD events (Trpkovic et al. 2015).
CRP and Infection
CRP in Connection with Diabetes Mellitus and Metabolic Syndrome
Low-grade inflammation leads to the development of cardiovascular diseases, metabolic syndrome, and diabetes mellitus type 2. Prospective study done by Pradhan et al. (2001) reported that elevated level of CRP, known inflammation marker, is a strong independent risk predictor of type 2 diabetes onset. After this study, significant number of investigators reported association between CRP level and insulin resistance, metabolic syndrome, and type 2 diabetes (Fig. 1). Research performed on middle-aged men in Finland showed that subjects with CRP concentrations greater or equal to 3 mg/L had high risk to develop type 2 diabetes (Laaksonen et al. 2004). It has been proposed that factors associated with diabetes, such as high glucose level, adipokines, and free fatty acids stimulate production of CRP in endothelial and smooth muscle cells, as well as in macrophages. Interestingly, administration of estradiol to obese rats has antiatherogenic and anti-inflammatory effects accomplished through regulation of CRP level (Obradovic et al. 2015a). There are indications that CRP may have causal role in the development of insulin resistance. This role is accomplished through activation of extracellular signal-regulated kinases 1 and 2 (Xi et al. 2006).
CRP and Cancer
It is well known that inflammation has an important role during carcinogenesis. Given that, question regarding potential association between CRP level and cancer onset emerged. Previous studies found no evidence for causal relationship between CRP level and neoplastic transformation (Allin and Nordestgaard 2011) (Fig. 1). However, it has been shown that elevated concentrations of CRP were associated with increased risk of many types of solid tumors (Allin and Nordestgaard 2011). Increased level of CRP correlates with poor prognosis in patients with breast and colorectal cancer. Additionally, CRP concentration level is associated with tumor stage and recurrence of the latter. In line with these findings, investigations showed that elevated CRP correlates with tumor size and stage of nonsmall cell lung cancer (Aref and Refaat 2014). There are two possible explanations for increased level of CRP in cancer patients (Aref and Refaat 2014). The first explanation is that increased level of circulating CRP is a consequence of production of cytokines in tumor tissues, while the second one is related to infections in cancer patients.
CRP and Atherosclerosis
Atherosclerosis is an inflammatory disease and the underlying cause of a number of cardiovascular disorders (Obradovic et al. 2015b). It is established that atherosclerosis is characterized by low-grade inflammation which is sustained by elevated levels of cytokines and acute-phase proteins. Among latter potential role and functions of CRP in atherogenesis still attract the most attention of scientific community. The first article clearly stated possible association between atherosclerosis and CRP concentration level was published in 1982. From that time, results of many epidemiological studies suggested that subjects with elevated CRP have increased risk of acute coronary syndrome, heart failure, myocardial infarction, peripheral artery, and coronary heart disease (Zimmermann et al. 2014). Investigations conducted within Physicians Health Study (1997) and Cholesterol and Recurrent Events trial (1998) showed that CRP level could be useful as a predictor of therapy efficiency on patients with vascular risk (Ridker 2009). Furthermore, JUPITER trial showed large benefit of rosuvastatin therapy among apparently health subjects with low or average level of LDL, but elevated level of CRP. Namely, administration of rosuvastatin during follow-up period dramatically lowered incidence of cardiovascular events: myocardial infarction rate decreased 54%, stroke rate decreased 48%, need for arterial revascularization decreased 46%, and all-cause mortality dropped by 20% (Ridker 2009). The results of the study suggest that statins decrease CRP level independent of LDL concentration.
Consideration of possible role of CRP in the process of atherosclerotic lesion formation is based on three observations: (a) CRP activates system complement pathway, (b) CRP binds to LDL molecule and facilitates its uptake by macrophages, and (c) CRP reduces the expression of nitric oxide synthase and prostacyclin synthase. Listed actions of CRP have direct proatherogenic effects. However, results of some studies showed that overexpression of human CRP had no proatherogenic effect in experimental animals. In line with this, results of some genetic studies failed to establish association between CRP gene polymorphism and vascular risk despite the association between the polymorphism and increased plasma CRP concentration (Obradovic et al. 2015b) (Fig. 1). Such result leads some authors to conclude that CRP has no causal role in atherosclerosis (Trpkovic et al. 2015).
C Reactive Protein belongs to a highly conserved protein family named pentraxins, which is involved in acute-phase response (inflammation, infection, neoplasia) in endothermic animals and humans. Its structure is represented by symmetric pentamer that has five identical 24 k-Da subunits containing 206 amino acids. CRP is predominantly synthesized in hepatocytes and in physiological conditions it is produced in relatively low rates and stored in the endoplasmic reticulum (ER). Large amounts of CRP (up to 1000-fold) are released into the circulation from ER, as a response to inflammation. As CRP is a widely used as biomarker of inflammation, its blood levels increase gradually. Significant number of investigators reported association between CRP level and insulin resistance, metabolic syndrome, type 2 diabetes, atherosclerosis, and malignancies.
This work is supported by grants No.173033 (to E.R.I) from the Ministry of Science, Republic of Serbia.
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