Chapter 5 Proinflammatory cytokines in CRP baseline regulation

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1. Abstract

Low‐grade inflammation, a minor elevation in the baseline concentration of inflammatory markers such as C‐reactive protein (CRP), is nowadays recognized as an important underlying condition in many common diseases. Concentrations of CRP under 10 mg/l are called low‐grade inflammation and values above that are considered as clinically significant inflammatory states. Epidemiological studies have revealed demographic and socioeconomic factors that associate with CRP concentration; these include age, sex, birth weight, ethnicity, socioeconomic status, body mass index (BMI), fiber consumption, alcohol intake, and dietary fatty acids. At the molecular level, production of CRP is induced by proinflammatory cytokines IL‐1, IL‐6, and IL‐17 in the liver, although extra hepatic production most likely contributes to systemic concentrations. The cytokines are produced in response to, for example, steroid hormones, thrombin, C5a, bradykinin, other cytokines, UV‐light, neuropeptides and bacterial components, such as lipopolysaccharide. Cytokines exert their biological effects on CRP by signaling through their receptors on hepatic cells and activating different kinases and phosphatases leading to translocation of various transcription factors on CRP gene promoter and production of CRP protein. Genetic polymorphisms in the interleukin genes as well as in CRP gene have been associated with minor elevation in CRP. As minor elevation in CRP is associated with both inflammatory and noninflammatory conditions, it should be noticed that the elevation might just reflect distressed or injured cells homeostasis maintenance in everyday life, rather than inflammation with classical symptoms of redness, swelling, heat, and pain.

Section snippets

C‐Reactive Protein and Inflammation

CRP is classified as one of the classical acute‐phase proteins by its biological properties. It is synthesized and secreted to the blood by the liver after initiating signals from the body, for example, infection, trauma, or tissue damage, mediated by inflammatory cytokines. By structure, CRP belongs to pentraxin protein family and is part of the soluble innate immune system where it plays an important role as a pattern‐recognition molecule [1]. After binding a ligand, for example,

Demographic, Metabolic, and Socioeconomic Factors

Population studies have shown that serum CRP concentrations are broadly distributed and highly skewed to the right in apparently healthy people [[32], [58]], that is, most individuals are grouped together in the lowest values measured, the rest being dispersed up to 10 mg/l or more. CRP concentrations have been found to increase slightly with age and to differ between males and females [[59], [60]], females tending to have slightly increased concentrations compared to males [[61], [62]].

Proinflammatory Cytokines

The main proinflammatory cytokine inducers of CRP in hepatic cells are the interleukins‐1 (IL‐1) and ‐6 (IL‐6) and recently found IL‐17. Generally, cytokines transduce signals from outside the cell into the cells via specific receptors. Compared to hormone or growth or factor receptors, the number of cytokine receptors on cell surfaces is usually a hundred time less than that of hormone or growth factor receptors [103]. Inside the cells, a given set of kinases, phosphatases and transcription

Signaling Through IL Receptors

Signaling from the IL receptors to CRP induction is done through several signaling molecules and transcription factors. The regulation of CRP expression is done at transcriptional level and focuses on the 300‐bp long CRP promoter. Most of the CRP expression studies have been done in Hep3B cells, and these are described below.

The promoter region of CRP of Hep3B cells harbors binding sites for transcription factors HNF‐1α (hepatic nuclear factor 1α), OCT‐1 (octamer-binding transcription factor

Genetic Polymorphisms

Serum CRP concentrations are influenced by genetic polymorphisms of various genes. Polymorphisms of several proinflammatory cytokine genes have been reported to associate with CRP concentration. A summary of these studies is presented in Table 1. Majority of the studies are quite small, and adjustment for covariates is lacking in many papers. Besides cytokine genes, polymorphisms in other genes also show association with CRP concentrations, including CRP, LEPR, HNF1A, APOE, GCKR, IRAK1, FTO [

Conclusions

Low grade inflammation is being accepted to lie behind many common diseases. However, it should be kept in mind that minor elevation in one of the major inflammatory markers measured in clinical practice today, CRP, can be the result of physiological homeostasis maintenance caused by minor tissue damage in our everyday life, reflecting CRP's role as a waste management molecule helping phagocytes remove cellular debris. Infection or a full blown inflammation with classical symptoms of redness,

Acknowledgment

I would like to thank Prof. M Hurme for valuable discussions during the manuscript preparation.

References (186)

  • D.G. Yanbaeva et al.

    Systemic effects of smoking

    Chest

    (2007)
  • D.J. Baer et al.

    Dietary fatty acids affect plasma markers of inflammation in healthy men fed controlled diets: a randomized crossover study

    Am. J. Clin. Nutr.

    (2004)
  • A. Zampelas et al.

    Associations between coffee consumption and inflammatory markers in healthy persons: the ATTICA study

    Am. J. Clin. Nutr.

    (2004)
  • A. Imhof et al.

    Effect of alcohol consumption on systemic markers of inflammation

    Lancet

    (2001)
  • U.A. Ajani et al.

    Dietary fiber and C‐reactive protein: findings from national health and nutrition examination survey data

    J. Nutr.

    (2004)
  • D.E. King et al.

    Relation of dietary fat and fiber to elevation of C‐reactive protein

    Am. J. Cardiol.

    (2003)
  • Y. Ma et al.

    Association between dietary fiber and markers of systemic inflammation in the Women's Health Initiative Observational Study

    Nutrition

    (2008)
  • S.S. Anand et al.

    Differences in risk factors, atherosclerosis, and cardiovascular disease between ethnic groups in Canada: the Study of Health Assessment and Risk in Ethnic groups (SHARE)

    Lancet

    (2000)
  • A.P. Simopoulos

    Evolutionary aspects of diet, the omega‐6/omega‐3 ratio and genetic variation: nutritional implications for chronic diseases

    Biomed. Pharmacother.

    (2006)
  • E. Lopez-Garcia et al.

    Major dietary patterns are related to plasma concentrations of markers of inflammation and endothelial dysfunction

    Am. J. Clin. Nutr.

    (2004)
  • T.T. Fung et al.

    Diet-quality scores and plasma concentrations of markers of inflammation and endothelial dysfunction

    Am. J. Clin. Nutr.

    (2005)
  • A.H. Lichtenstein et al.

    Influence of hydrogenated fat and butter on CVD risk factors: remnant-like particles, glucose and insulin, blood pressure and C‐reactive protein

    Atherosclerosis

    (2003)
  • C. Chrysohoou et al.

    Adherence to the Mediterranean diet attenuates inflammation and coagulation process in healthy adults: the ATTICA Study

    J. Am. Coll. Cardiol.

    (2004)
  • S. Cinti et al.

    Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans

    J. Lipid. Res.

    (2005)
  • G. Charriere et al.

    Preadipocyte conversion to macrophage. Evidence of plasticity

    J. Biol. Chem.

    (2003)
  • Y. Ma et al.

    Association between dietary fiber and serum C‐reactive protein

    Am. J. Clin. Nutr.

    (2006)
  • S. Liu

    Whole-grain foods, dietary fiber, and type 2 diabetes: searching for a kernel of truth

    Am. J. Clin. Nutr.

    (2003)
  • C.A. Janeway et al.

    Innate immune recognition

    Annu. Rev. Immunol.

    (2002)
  • J.E. Volanakis et al.

    Specificity of C‐reactive protein for choline phosphate residues of pneumococcal C‐polysaccharide

    Proc. Soc. Exp. Biol. Med.

    (1971)
  • T.W. Du Clos et al.

    Analysis of the binding of C‐reactive protein to histones and chromatin

    J. Immunol.

    (1988)
  • S.J. Swanson et al.

    Characteristics of the binding of human C‐reactive protein (CRP) to laminin

    J. Cell Biochem.

    (1989)
  • T.W. Du Clos

    C‐reactive protein reacts with the U1 small nuclear ribonucleoprotein

    J. Immunol.

    (1989)
  • M.P. Stein et al.

    C‐reactive protein binding to FcgammaRIIa on human monocytes and neutrophils is allele‐specific

    J. Clin. Invest.

    (2000)
  • F.C. de Beer et al.

    Low density lipoprotein and very low density lipoprotein are selectively bound by aggregated C‐reactive protein

    J. Exp. Med.

    (1982)
  • J.E. Volanakis et al.

    Interaction of C‐reactive protein with artificial phosphatidylcholine bilayers

    Nature

    (1979)
  • A.J. Narkates et al.

    C‐reactive protein binding specificities: artificial and natural phospholipid bilayers

    Ann. N. Y. Acad. Sci.

    (1982)
  • D. Gershov et al.

    C‐Reactive protein binds to apoptotic cells, protects the cells from assembly of the terminal complement components, and sustains an antiinflammatory innate immune response: implications for systemic autoimmunity

    J. Exp. Med.

    (2000)
  • M.K. Chang et al.

    C‐reactive protein binds to both oxidized LDL and apoptotic cells through recognition of a common ligand: phosphorylcholine of oxidized phospholipids

    Proc. Natl. Acad. Sci. USA

    (2002)
  • Y.P. Li et al.

    Sublytic complement attack exposes C‐reactive protein binding sites on cell membranes

    J. Immunol.

    (1994)
  • J.E. Volanakis et al.

    Interaction of C‐reactive protein with artificial phosphatidylcholine bilayers and complement

    J. Immunol.

    (1981)
  • A.J. Szalai

    C-reactive protein (CRP) and autoimmune disease: facts and conjectures

    Clin. Dev. Immunol.

    (2004)
  • C. Nathan

    Points of control in inflammation

    Nature

    (2002)
  • G.M. Barton

    A calculated response: control of inflammation by the innate immune system

    J. Clin. Invest.

    (2008)
  • C.J. Chen et al.

    Identification of a key pathway required for the sterile inflammatory response triggered by dying cells

    Nat. Med.

    (2007)
  • D.E. Laaksonen et al.

    C-reactive protein and the development of the metabolic syndrome and diabetes in middle-aged men

    Diabetologia

    (2004)
  • A.D. Pradhan et al.

    C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus

    J. Am. Med. Assoc.

    (2001)
  • A. Festa et al.

    Chronic subclinical inflammation as part of the insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS)

    Circulation

    (2000)
  • G.K. Hansson

    Inflammation, atherosclerosis, and coronary artery disease

    N. Engl. J. Med.

    (2005)
  • R. Ross

    Atherosclerosis—an inflammatory disease

    N. Engl. J. Med.

    (1999)
  • K. Heikkila et al.

    Associations of circulating C‐reactive protein and interleukin‐6 with cancer risk: findings from two prospective cohorts and a meta-analysis

    Cancer Causes Control

    (2009)
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