Inflammatory C-Reactive Protein (CRP)

Also see:
Endotoxin: Poisoning from the Inside Out
Ray Peat, PhD on Endotoxin
Exercise and Endotoxemia
Anti-Inflammatory Omega -9 Mead Acid (Eicosatrienoic acid)

“Systemic metabolic problems make local problems worse, and if a local injury is serious, it can cause the liver to produce stress-related proteins called “acute phase proteins,” including fibrinogen and serum amyloids A and P, C-reactive protein, and other inflammation-related proteins. These proteins are a primitive sort of immune system, that· can directly bind to some harmful substances. Endotoxin absorbed from bowel bacteria is probably the commonest reason for increased production of these proteins. The acute phase proteins contribute to the development of tumors in various ways. For example fibrinogen degradation products are pro-inflammatory. Although these are called acute phase proteins, they sometimes might better be called chronic inflammation proteins, since they are associated with diabetes, cancer, and heart disease.” -Ray Peat, PhD

J Clin Endocrinol Metab. 2001 Sep;86(9):4216-22.
Differential effects of E and droloxifene on C-reactive protein and other markers of inflammation in healthy postmenopausal women.
Herrington DM, Brosnihan KB, Pusser BE, Seely EW, Ridker PM, Rifai N, MacLean DB.
Although increased levels of C-reactive protein have been linked to E therapy, the significance of this finding and whether it occurs with the selective ER modulators are unknown. Thirty-five healthy postmenopausal women were enrolled in a placebo-controlled, two-period cross-over design trial to evaluate the effects of 0.625 mg oral conjugated E and 60 mg droloxifene, a structural analog of tamoxifen, on serum levels of C-reactive protein, IL-6, and endothelial cell adhesion molecules. E treatment resulted in 65.8% higher levels of C-reactive protein (P = 0.0002) and 48.1% higher levels of IL-6 (P < 0.001), but also resulted in a 10.9% reduction in soluble E-selectin (P = 0.002) and borderline reductions in vascular cell adhesion molecule-1. In contrast, droloxifene had no effect on C-reactive protein and IL-6, but did produce a significant 11% reduction in E-selectin (P < 0.00001). However, droloxifene also resulted in an 11.6% increase in vascular cell adhesion molecule-1 (P < 0.007). These data provide additional evidence of a proinflammatory effect of E that may have adverse cardiovascular consequences. However, these changes were also accompanied by a reduction in E-selectin, suggesting an antiinflammatory effect at the level of the endothelium. The net clinical impact of these changes is not yet well established. In contrast, droloxifene had little or no proinflammatory effects on C-reactive protein and IL-6 and had mixed effects on endothelial adhesion molecules. This observation provides additional rationale for continuing to evaluate the potential cardiovascular benefits of selective ER modulators.

Am J Pathol. 2001 Mar;158(3):1039-51.
Generation of C-reactive protein and complement components in atherosclerotic plaques.
Yasojima K, Schwab C, McGeer EG, McGeer PL.
C-reactive protein (CRP) and complement are hypothesized to be major mediators of inflammation in atherosclerotic plaques. We used the reverse transcriptase-polymerase chain reaction technique to detect the mRNAs for CRP and the classical complement components C1 to C9 in both normal arterial and plaque tissue, establishing that they can be endogenously generated by arteries. When the CRP mRNA levels of plaque tissue, normal artery, and liver were compared in the same cases, plaque levels were 10.2-fold higher than normal artery and 7.2-fold higher than liver. By Western blotting, we showed that the protein levels of CRP and complement proteins were also up-regulated in plaque tissue and that there was full activation of the classical complement pathway. By in situ hybridization, we detected intense signals for CRP and C4 mRNAs in smooth muscle-like cells and macrophages in the thickened intima of plaques. By immunohistochemistry we showed co-localization of CRP and the membrane attack complex of complement. We also detected up-regulation in plaque tissue of the mRNAs for the macrophage markers CD11b and HLA-DR, as well as their protein products. We showed by immunohistochemistry macrophage infiltration of plaque tissue. Because CRP is a complement activator, and activated complement attacks cells in plaque tissue, these data provide evidence of a self-sustaining autotoxic mechanism operating within the plaques as a precursor to thrombotic events.

Ital Heart J. 2001 Mar;2(3):196-9.
C-reactive protein and atherothrombosis.
Pepys MB, Hirschfield GM.
Circulating concentrations of C-reactive protein (CRP), the classical acute phase protein and sensitive systemic marker of inflammation, significantly predict atherothrombotic events and outcome after acute myocardial infarction, demonstrating the key role of inflammation in atherosclerosis and its complications. The binding specificity of CRP for low density lipoproteins, for modified low density lipoproteins, and for damaged and dead cells, coupled with the capacity of bound CRP to activate complement, and with the presence of CRP in atheroma and acute myocardial infarction lesions, all suggest a possible pathogenetic role of CRP. Development of drugs to block binding of CRP to its various ligands in vivo will enable this hypothesis to be tested.

Hypertension. 2004 Jul;44(1):6-11. Epub 2004 May 17.
C-reactive protein: risk marker or mediator in atherothrombosis?
Jialal I, Devaraj S, Venugopal SK.
Inflammation appears to be pivotal in all phases of atherosclerosis from the fatty streak lesion to acute coronary syndromes. An important downstream marker of inflammation is C-reactive protein (CRP). Numerous studies have shown that CRP levels predict cardiovascular disease in apparently healthy individuals. This has resulted in a position statement recommending cutoff levels of CRP <1.0, 1.0 to 3.0, and >3.0 mg/L equating to low, average, and high risk for subsequent cardiovascular disease. More interestingly, much in vitro data have now emerged in support of a role for CRP in atherogenesis. To date, studies largely in endothelial cells, but also in monocyte-macrophages and vascular smooth muscle cells, support a role for CRP in atherogenesis. The proinflammatory, proatherogenic effects of CRP that have been documented in endothelial cells include the following: decreased nitric oxide and prostacyclin and increased endothelin-1, cell adhesion molecules, monocyte chemoattractant protein-1 and interleukin-8, and increased plasminogen activator inhibitor-1. In monocyte-macrophages, CRP induces tissue factor secretion, increases reactive oxygen species and proinflammatory cytokine release, promotes monocyte chemotaxis and adhesion, and increases oxidized low-density lipoprotein uptake. Also, CRP has been shown in vascular smooth muscle cells to increase inducible nitric oxide production, increase NFkappa(b) and mitogen-activated protein kinase activities, and, most importantly, upregulate angiotensin type-1 receptor resulting in increased reactive oxygen species and vascular smooth muscle cell proliferation. Future studies should be directed at delineating the molecular mechanisms for these important in vitro observations. Also, studies should be directed at confirming these findings in animal models and other systems as proof of concept. In conclusion, CRP is a risk marker for cardiovascular disease and, based on future studies, could emerge as a mediator in atherogenesis.

J Periodontol. 2008 Aug;79(8 Suppl):1544-51. doi: 10.1902/jop.2008.080249.
Inflammation, C-reactive protein, and atherothrombosis.
Ridker PM, Silvertown JD.
Atherothrombosis of the coronary and cerebral vessels is understood to be a disorder of inflammation and innate immunity, as well as a disorder of lipid accumulation. From a vascular biology perspective, the processes of cellular adhesion, monocyte and macrophage attachment, and transmigration of immune cells across the endothelium are crucial steps in early atherogenesis and in the later stages of mature plaque rupture, particularly the transition of unstable plaque at the time of acute thrombosis. There is abundant clinical evidence demonstrating that many biomarkers of inflammation are elevated years in advance of first ever myocardial infarction (MI) or thrombotic stroke and that these same biomarkers are highly predictive of recurrent MI, recurrent stroke, diabetes, and cardiovascular death. In daily practice, the inflammatory biomarker in widest use is high-sensitivity C-reactive protein (hsCRP); when interpreted within the context of usual risk factors, levels of hsCRP <1, 1 to 3, and >3 mg/l denote lower, average, and higher relative risk for future vascular events. Risk-prediction models that incorporate hsCRP, such as the Reynolds Risk Score, have been developed that improve risk classification and the accuracy for global risk prediction, particularly for those deemed at “intermediate risk” by usual algorithms, such as the Framingham Risk Score. With regard to cerebral vessels, increased biomarkers of inflammation, including hsCRP, have been associated with increased stroke risk as well as an increased rate of atherosclerosis progression in the carotid vessels. Although the proportion of variation in hsCRP explained by genetic factors may be as large as 20% to 40%, diet, exercise, and smoking cessation remain critical tools for risk reduction and CRP reduction. Statin therapy reduces hsCRP in a largely low-density lipoprotein (LDL)-independent manner, and the “anti-inflammatory” properties of these agents have been suggested as a potential mechanism beyond LDL reduction for the efficacy of these agents. The ongoing multinational Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial of 17,802 initially healthy men and women with low levels of LDL cholesterol but increased levels of hsCRP will help to define whether vascular protection can be achieved with statin therapy, even in the absence of hyperlipidemia. Targeted anti-inflammatory therapies are being developed that may provide a direct method of translating the biology of inflammation into new clinical treatments across multiple vascular beds. This article summarizes data supporting a role for inflammation in cardiovascular disease and offers the possibility that other disorders characterized by inflammation, such as periodontal disease, may have an indirect role by influencing the risk, manifestation, and progression of vascular events.

JAMA. 2001 Jul 18;286(3):327-34.
C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus.
Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM.
Inflammation is hypothesized to play a role in development of type 2 diabetes mellitus (DM); however, clinical data addressing this issue are limited.
To determine whether elevated levels of the inflammatory markers interleukin 6 (IL-6) and C-reactive protein (CRP) are associated with development of type 2 DM in healthy middle-aged women.
Prospective, nested case-control study.
The Women’s Health Study, an ongoing US primary prevention, randomized clinical trial initiated in 1992.
From a nationwide cohort of 27 628 women free of diagnosed DM, cardiovascular disease, and cancer at baseline, 188 women who developed diagnosed DM over a 4-year follow-up period were defined as cases and matched by age and fasting status with 362 disease-free controls.
Incidence of confirmed clinically diagnosed type 2 DM by baseline levels of IL-6 and CRP.
Baseline levels of IL-6 (P<.001) and CRP (P<.001) were significantly higher among cases than among controls. The relative risks of future DM for women in the highest vs lowest quartile of these inflammatory markers were 7.5 for IL-6 (95% confidence interval [CI], 3.7-15.4) and 15.7 for CRP (95% CI, 6.5-37.9). Positive associations persisted after adjustment for body mass index, family history of diabetes, smoking, exercise, use of alcohol, and hormone replacement therapy; multivariate relative risks for the highest vs lowest quartiles were 2.3 for IL-6 (95% CI, 0.9-5.6; P for trend =.07) and 4.2 for CRP (95% CI, 1.5-12.0; P for trend =.001). Similar results were observed in analyses limited to women with a baseline hemoglobin A(1c) of 6.0% or less and after adjustment for fasting insulin level. CONCLUSIONS: Elevated levels of CRP and IL-6 predict the development of type 2 DM. These data support a possible role for inflammation in diabetogenesis.

Thromb Haemost. 1999 Jun;81(6):925-8.
Increased C-reactive protein levels during short-term hormone replacement therapy in healthy postmenopausal women.
van Baal WM, Kenemans P, van der Mooren MJ, Kessel H, Emeis JJ, Stehouwer CD.
To study the short-term effect of unopposed oestradiol (E2) and sequentially combined hormone replacement therapy (E2 + P) on C-reactive protein (CRP) in healthy postmenopausal women.
Prospective, randomised, placebo-controlled 12-week study. Sixty healthy. normotensive, non-hysterectomised postmenopausal women received either placebo (N = 16) or daily 2 mg micronised oestradiol, either unopposed (N = 16, E2 group) or sequentially combined with a progestagen on 14 days of each cycle (N = 28, E2+P group). Data were collected at baseline and at 4 and 12 weeks.
CRP levels increased significantly during the 12 weeks in the E2 and the E2+P groups compared to placebo. No differences were found between the E2 group and the E2+P group [E2 and E2+P group together (N = 44) versus placebo: P = 0.01; E2 versus E2+P: P = 0.75]. To give a quantitative estimate of the increase, the median change calculated from baseline in both treatment groups together was +87% (P = 0.02) at 4 weeks, and +114% (P = 0.08) at 12 weeks, as compared to the placebo group.
In healthy postmenopausal women, short-term treatment with E2 or E2+P was associated with a rapid rise in CRP concentrations. These observations raise the possibility that the increased risk of cardiovascular events is related to an initial increase in CRP levels after starting hormone replacement therapy.

Clin J Sport Med. 2001 Jan;11(1):38-43.
The acute phase response and exercise: the ultramarathon as prototype exercise.
Fallon KE.
Controversy exists in relation to the nature of the acute phase response, which is known to occur following endurance exercise. This study was conducted to demonstrate the similarities between this response and the response consequent to general medical and surgical conditions.
This is a case series field study of serum levels of acute phase reactants in a group of ultramarathon runners competing in a 6-day track race.
Seven male and one female experienced ultramarathon runners.
A track race of 6 days duration.
Serum iron, ferritin, transferrin, albumin, haptoglobin, alpha-1 antitrypsin, complement components 3 and 4, C-reactive protein, and erythrocyte sedimentation rate, total iron binding capacity, and transferrin saturation.
Of the 11 acute phase reactants measured, 6 (serum iron, ferritin, percent transferrin saturation, C-reactive protein, erythrocyte sedimentation rate, and haptoglobin) responded as if an acute phase response was present; 5 (tranferrin, albumin, alpha-1 antitrypsin, and complement components 3 and 4) did not respond in such a fashion.
This study provides further evidence that the acute phase response consequent to exercise is analogous to that which occurs in general medical and surgical conditions. The previous demonstration of the presence of the appropriate cytokines following exercise, the findings of others in relation to acute phase reactants not the subjects of this study, the possibility that a training effect leading to attenuation of the response and the realization that the acute phase response is not identical across a range of medical conditions lends weight to the above conclusion.


“Many types of evidence indicate that environmental PUFA and prostaglandins produced from the “essential” fatty acids are required for inflammation to progress to degeneration. The n-9 polyunsaturated tatty acids (the kind we can make make from saturated fat or sugar) seems to be positively protective against inflammation. For example, rats fed a diet with 2% hydrogenated coconut oil for two weeks had lower levels of IL-6 and C-reactive protein than when a small amount of arachidonic acid and docosahexaenoic acid (DHA) were added. Mead acid (20:3n9) was lower in the group with the PUFA supplement, and the inflammatory reaction to endotoxin was greater in the supplemented group (Ling, et aI., 2012).” -Ray Peat, PhD

Metabolism. 2012 Mar;61(3):395-406. Epub 2011 Sep 23.
Arachidonic acid and docosahexaenoic acid supplemented to an essential fatty acid-deficient diet alters the response to endotoxin in rats.
Ling PR, Malkan A, Le HD, Puder M, Bistrian BR.
This study examined fatty acid profiles, triene-tetraene ratios (20:3n9/20:4n6), and nutritional and inflammatory markers in rats fed an essential fatty acid-deficient (EFAD) diet provided as 2% hydrogenated coconut oil (HCO) alone for 2 weeks or with 1.3 mg of arachidonic acid (AA) and 3.3 mg of docosahexaenoic acid (DHA) (AA + DHA) added to achieve 2% fat. Healthy controls were fed an AIN 93M diet (AIN) with 2% soybean oil. The HCO and AA + DHA diets led to significant reductions of linoleic acid, α-linolenic acid, and AA (20:4n6) and increases in Mead acid (20:3n9) in plasma and liver compared with the AIN diet; but the triene-tetraene levels remained well within normal. However, levels of 20:3n9 and 20:4n6 were lower in liver phospholipids in the AA + DHA than in HCO group, suggesting reduced elongation and desaturation in ω-9 and -6 pathways. The AA + DHA group also had significantly lower levels of 18:1n9 and 16:1n7 as well as 18:1n9/18:0 and 16:1n7/16:0 than the HCO group, suggesting inhibition of stearyl-Co A desaturase-1 activity. In response to lipopolysaccharide, the levels of tumor necrosis factor and interleukin-6 were significantly lower with HCO, reflecting reduced inflammation. The AA + DHA group had higher levels of IL-6 and C-reactive protein than the HCO group but significantly lower than the AIN group. However, in response to endotoxin, interleukin-6 was higher with AA + DHA than with AIN. Feeding an EFAD diet reduces baseline inflammation and inflammatory response to endotoxin long before the development of EFAD, and added AA + DHA modifies this response.

Posted in General.

Tagged with , , , , , , , , , , , , , , , , , , , , , , .