Exercise and Toll-like receptors Running Head : Exercise and TLRs

Toll-like receptors (TLRs) are highly conserved trans-membrane proteins that play an important role in the detection and recognition of microbial pathogens. The key product of TLR signalling in antigen presenting cells is the production of inflammatory cytokines and proteins. The TLR pathway plays an important role in mediating whole body inflammation, which has been implicated in the development of chronic disease. An accumulation of chronic, low-grade inflammation is common in individuals that live a sedentary lifestyle; however, the mechanism underlying this connection is not fully understood. There is evidence to show that TLRs may be involved in the link between a sedentary lifestyle, inflammation, and disease. Recent studies have shown that both acute aerobic and chronic resistance exercise resulted in decreased monocyte cell-surface expression of TLRs. Furthermore, a period of chronic exercise training decreases both inflammatory cytokine production and the cell-surface expression of TLR4 on monocytes. These effects may contribute to post-exercise immunodepression and the reported higher susceptibility to infection in athletes. However, over the long term, a decrease in TLR expression may represent a beneficial effect because it decreases the inflammatory capacity of leukocytes, thus altering whole body chronic inflammation. The precise physiological stimulus mediating an exercise-induced decrease in cell-surface TLR expression is not known; however, a number of possible signals have been implicated including anti-inflammatory cytokines, stress hormones and heat shock proteins. (Exerc. Immunol. Rev. 12, 2006: 34-53)

[1]  C. Franceschi,et al.  Inflamm-aging, cytokines and aging: state of the art, new hypotheses on the role of mitochondria and new perspectives from systems biology. , 2006, Current pharmaceutical design.

[2]  S. Akira,et al.  Innate immune recognition of viral infection. , 2006, Nature immunology.

[3]  S. Akira,et al.  Toll-like receptor function and signaling. , 2006, The Journal of allergy and clinical immunology.

[4]  C. Caruso,et al.  Inflammation, Longevity, and Cardiovascular Diseases , 2006, Annals of the New York Academy of Sciences.

[5]  J. Paul Robinson,et al.  Physical activity status, but not age, influences inflammatory biomarkers and toll-like receptor 4. , 2006, The journals of gerontology. Series A, Biological sciences and medical sciences.

[6]  R. Paschke,et al.  Effect of a 4 week physical training program on plasma concentrations of inflammatory markers in patients with abnormal glucose tolerance. , 2006, European journal of endocrinology.

[7]  M. Netea,et al.  Recognition of pathogenic microorganisms by Toll-like receptors. , 2006, Drugs of today.

[8]  B. Saltin,et al.  Evidence for prescribing exercise as therapy in chronic disease , 2006, Scandinavian journal of medicine & science in sports.

[9]  H. White,et al.  Effects of exercise training on 5 inflammatory markers associated with cardiovascular risk. , 2006, American heart journal.

[10]  E. Kovacs,et al.  Aging negatively skews macrophage TLR2- and TLR4-mediated pro-inflammatory responses without affecting the IL-2-stimulated pathway , 2005, Mechanisms of Ageing and Development.

[11]  R. Busse,et al.  Preadipocytes in the human subcutaneous adipose tissue display distinct features from the adult mesenchymal and hematopoietic stem cells , 2005, Journal of cellular physiology.

[12]  J. Paul Robinson,et al.  Influence of exercise training and age on CD14+ cell-surface expression of toll-like receptor 2 and 4 , 2005, Brain, Behavior, and Immunity.

[13]  B. Fernhall,et al.  Effects of diet and/or exercise on the adipocytokine and inflammatory cytokine levels of postmenopausal women with type 2 diabetes. , 2005, Metabolism: clinical and experimental.

[14]  G. Fantuzzi Adipose tissue, adipokines, and inflammation. , 2005, The Journal of allergy and clinical immunology.

[15]  R. Flavell,et al.  IL-1 receptor–associated kinase M is a central regulator of osteoclast differentiation and activation , 2005, The Journal of experimental medicine.

[16]  Xuetao Cao,et al.  Heat shock up‐regulates expression of Toll‐like receptor‐2 and Toll‐like receptor‐4 in human monocytes via p38 kinase signal pathway , 2005, Immunology.

[17]  A. Jeukendrup,et al.  The physiological regulation of toll‐like receptor expression and function in humans , 2005, The Journal of physiology.

[18]  B. Horne,et al.  Toll-like receptor 4 gene Asp299Gly polymorphism is associated with reductions in vascular inflammation, angiographic coronary artery disease, and clinical diabetes. , 2004, American heart journal.

[19]  Ruslan Medzhitov,et al.  Toll-like receptors: linking innate and adaptive immunity. , 2005, Advances in experimental medicine and biology.

[20]  S. Akira,et al.  Toll-like receptors in innate immunity. , 2004, International immunology.

[21]  C. Franceschi,et al.  Role of Toll-like receptor 4 in acute myocardial infarction and longevity. , 2004, JAMA.

[22]  W. Campbell,et al.  TLR4 is lower in resistance-trained older women and related to inflammatory cytokines. , 2004, Medicine and science in sports and exercise.

[23]  G. De Backer,et al.  Association between leisure time physical activity and markers of chronic inflammation related to coronary heart disease. , 2004, Atherosclerosis.

[24]  W. Markiewicz,et al.  C-Reactive protein is inversely related to physical fitness in middle-aged subjects. , 2004, Atherosclerosis.

[25]  B. Nicklas,et al.  Reductions in plasma cytokine levels with weight loss improve insulin sensitivity in overweight and obese postmenopausal women. , 2004, Diabetes care.

[26]  D. Reen,et al.  HSP60 induces self‐tolerance to repeated HSP60 stimulation and cross‐tolerance to other pro‐inflammatory stimuli , 2004, European journal of immunology.

[27]  E. Bleecker,et al.  Diet-induced weight loss, exercise, and chronic inflammation in older, obese adults: a randomized controlled clinical trial. , 2004, The American journal of clinical nutrition.

[28]  B. Nicklas,et al.  Effects of hypocaloric diet and exercise training on inflammation and adipocyte lipolysis in obese postmenopausal women. , 2004, The Journal of clinical endocrinology and metabolism.

[29]  R. Flavell,et al.  Toll-like receptors 9 and 3 as essential components of innate immune defense against mouse cytomegalovirus infection. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[30]  D. E. Faunce,et al.  Age‐dependent decrease in Toll‐like receptor 4‐mediated proinflammatory cytokine production and mitogen‐activated protein kinase expression , 2004, Journal of leukocyte biology.

[31]  Shizuo Akira,et al.  TLR signaling pathways. , 2004, Seminars in immunology.

[32]  K. Timmerman,et al.  Toll-like receptor 4 and CD14 mRNA expression are lower in resistive exercise-trained elderly women. , 2003, Journal of applied physiology.

[33]  R. Holle,et al.  The endotoxin receptor TLR4 polymorphism is not associated with diabetes or components of the metabolic syndrome. , 2003, Diabetes.

[34]  A. Dominiczak,et al.  Strikingly Low Circulating CRP Concentrations in Ultramarathon Runners Independent of Markers of Adiposity: How Low Can You Go? , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[35]  Stefan W Krause,et al.  Species-specific Regulation of Toll-like Receptor 3 Genes in Men and Mice* , 2003, Journal of Biological Chemistry.

[36]  E. Minar,et al.  Impact of Weight Loss on Inflammatory Proteins and Their Association With the Insulin Resistance Syndrome in Morbidly Obese Patients , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[37]  S. Akira,et al.  Activation and regulation of Toll-like receptors 2 and 1 in human leprosy , 2003, Nature Medicine.

[38]  M. Schroll,et al.  Predicting death from tumour necrosis factor‐alpha and interleukin‐6 in 80‐year‐old people , 2003, Clinical and experimental immunology.

[39]  R. Gay,et al.  Expression and regulation of Toll-like receptor 2 in rheumatoid arthritis synovium. , 2003, The American journal of pathology.

[40]  T. Nishihara,et al.  Lipopolysaccharide Promotes the Survival of Osteoclasts Via Toll-Like Receptor 4, but Cytokine Production of Osteoclasts in Response to Lipopolysaccharide Is Different from That of Macrophages 1 , 2003, The Journal of Immunology.

[41]  邊見 弘明,et al.  A Toll-like receptor recognizes bacterial DNA , 2003 .

[42]  Ruslan Medzhitov,et al.  Toll Pathway-Dependent Blockade of CD4+CD25+ T Cell-Mediated Suppression by Dendritic Cells , 2003, Science.

[43]  Helle Bruunsgaard,et al.  Effects of tumor necrosis factor-alpha and interleukin-6 in elderly populations. , 2003, European cytokine network.

[44]  Jiahuai Han,et al.  Inhibition of p38 MAPK by Glucocorticoids via Induction of MAPK Phosphatase-1 Enhances Nontypeable Haemophilus influenzae-induced Expression of Toll-like Receptor 2* , 2002, The Journal of Biological Chemistry.

[45]  S. Akira,et al.  Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4 , 2002, Nature.

[46]  J. Katz,et al.  Cutting Edge: Impaired Toll-Like Receptor Expression and Function in Aging , 2002, The Journal of Immunology.

[47]  A. Humeny,et al.  Polymorphisms of TLR4: rapid genotyping and reduced response to lipopolysaccharide of TLR4 mutant alleles. , 2002, Clinical chemistry.

[48]  E. Ford Does Exercise Reduce Inflammation? Physical Activity and C-Reactive Protein Among U.S. Adults , 2002, Epidemiology.

[49]  Michael Rehli,et al.  Of mice and men: species variations of Toll-like receptor expression. , 2002, Trends in immunology.

[50]  E. Fikrig,et al.  Hyporesponsiveness to vaccination with Borrelia burgdorferi OspA in humans and in TLR1- and TLR2-deficient mice , 2002, Nature Medicine.

[51]  S. Akira,et al.  Cutting Edge: Role of Toll-Like Receptor 1 in Mediating Immune Response to Microbial Lipoproteins1 , 2002, The Journal of Immunology.

[52]  A. Sher,et al.  Cutting Edge: MyD88 Is Required for Resistance to Toxoplasma gondii Infection and Regulates Parasite-Induced IL-12 Production by Dendritic Cells1 , 2002, The Journal of Immunology.

[53]  H. Wagner,et al.  Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848 , 2002, Nature Immunology.

[54]  T. Espevik,et al.  The Proinflammatory CD14+CD16+DR++ Monocytes Are a Major Source of TNF1 , 2002, The Journal of Immunology.

[55]  G. Hansson,et al.  Expression of Toll-Like Receptors in Human Atherosclerotic Lesions: A Possible Pathway for Plaque Activation , 2002, Circulation.

[56]  S. Akira,et al.  Small anti-viral compounds activate immune cells via the TLR7 MyD88–dependent signaling pathway , 2002, Nature Immunology.

[57]  D. Franchimont,et al.  Gene profiling reveals unknown enhancing and suppressive actions of glucocorticoids on immune cells , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[58]  M. Fishbein,et al.  Toll-Like Receptor-4 Is Expressed by Macrophages in Murine and Human Lipid-Rich Atherosclerotic Plaques and Upregulated by Oxidized LDL , 2001, Circulation.

[59]  P. Wang,et al.  Heterogeneous expression of Toll-like receptor 4 and downregulation of Toll-like receptor 4 expression on human gingival fibroblasts by Porphyromonas gingivalis lipopolysaccharide. , 2001, Biochemical and biophysical research communications.

[60]  Ruslan Medzhitov,et al.  Toll-like receptors and innate immunity , 2001, Nature Reviews Immunology.

[61]  R. Flavell,et al.  Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3 , 2001, Nature.

[62]  I. Julkunen,et al.  IFNs activate toll-like receptor gene expression in viral infections , 2001, Genes and Immunity.

[63]  S. Akira,et al.  Toll-like receptors control activation of adaptive immune responses , 2001, Nature Immunology.

[64]  S. Akira,et al.  The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5 , 2001, Nature.

[65]  J. Smith,et al.  Exercise and Atherogenesis , 2001, Exercise and sport sciences reviews.

[66]  S. Akira,et al.  Toll-like receptors; their physiological role and signal transduction system. , 2001, International immunopharmacology.

[67]  S. Akira,et al.  [Induction of direct antimicrobial activity through mammalian toll-like receptors]. , 2001, Pneumologie.

[68]  S. Meydani,et al.  Interleukin-6 production does not increase with age. , 2001, The journals of gerontology. Series A, Biological sciences and medical sciences.

[69]  A. Aderem,et al.  The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between toll-like receptors. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[70]  T. Ogawa,et al.  Gene Expressions of Toll-Like Receptor 2, But Not Toll-Like Receptor 4, Is Induced by LPS and Inflammatory Cytokines in Mouse Macrophages1 , 2000, The Journal of Immunology.

[71]  S. Akira,et al.  Cutting Edge: TLR2-Deficient and MyD88-Deficient Mice Are Highly Susceptible to Staphylococcus aureus Infection1 , 2000, The Journal of Immunology.

[72]  S. Brod Unregulated inflammation shortens human functional longevity , 2000, Inflammation Research.

[73]  M. Mack,et al.  Selective mobilization of CD14(+)CD16(+) monocytes by exercise. , 2000, American journal of physiology. Cell physiology.

[74]  P. Allavena,et al.  Differential Expression and Regulation of Toll-Like Receptors (TLR) in Human Leukocytes: Selective Expression of TLR3 in Dendritic Cells1 , 2000, The Journal of Immunology.

[75]  H. Staege,et al.  Human toll-like receptors 2 and 4 are targets for deactivation of mononuclear phagocytes by interleukin-4. , 2000, Immunology letters.

[76]  M. Rothe,et al.  Peptidoglycan- and Lipoteichoic Acid-induced Cell Activation Is Mediated by Toll-like Receptor 2* , 1999, The Journal of Biological Chemistry.

[77]  S. Akira,et al.  Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. , 1999, Journal of immunology.

[78]  Peter Schjerling,et al.  Pro‐ and anti‐inflammatory cytokine balance in strenuous exercise in humans , 1999, The Journal of physiology.

[79]  P. Ricciardi-Castagnoli,et al.  Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. , 1998, Science.

[80]  R. Steinman,et al.  Dendritic cells and the control of immunity , 1998, Nature.

[81]  C. Janeway,et al.  A human homologue of the Drosophila Toll protein signals activation of adaptive immunity , 1997, Nature.

[82]  H. Ullum,et al.  Exercise-Induced Immunomodulation - Possible Roles of Neuroendocrine and Metabolic Factors , 1997, International journal of sports medicine.

[83]  H. Ziegler-Heitbrock,et al.  Heterogeneity of human blood monocytes: the CD14+ CD16+ subpopulation. , 1996, Immunology today.

[84]  B. Spiegelman,et al.  Tumor Necrosis Factor α: A Key Component of the Obesity-Diabetes Link , 1994, Diabetes.

[85]  H. Ullum,et al.  Bicycle exercise enhances plasma IL-6 but does not change IL-1 alpha, IL-1 beta, IL-6, or TNF-alpha pre-mRNA in BMNC. , 1994, Journal of applied physiology.

[86]  C. Franceschi,et al.  Increased cytokine production in mononuclear cells of healthy elderly people , 1993, European journal of immunology.

[87]  D. Nieman,et al.  Infectious episodes in runners before and after the Los Angeles Marathon. , 1990, The Journal of sports medicine and physical fitness.

[88]  E. Bateman,et al.  Ultramarathon running and upper respiratory tract infections. An epidemiological survey. , 1983, South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde.

[89]  S. Opal,et al.  Role of Toll-like receptors in infection and immunity: clinical implications. , 2006, Drugs.

[90]  B. Isermann,et al.  Asp299Gly and Thr399Ile genotypes of the TLR4 gene are associated with a reduced prevalence of diabetic neuropathy in patients with type 2 diabetes. , 2004, Diabetes care.

[91]  S. Akira,et al.  Toll-like receptors. , 2003, Annual review of immunology.

[92]  E. Keller,et al.  Age-associated increased interleukin-6 gene expression, late-life diseases, and frailty. , 2000, Annual review of medicine.

[93]  P. Wilson,et al.  Monocyte cytokine production in an elderly population: effect of age and inflammation. , 1998, The journals of gerontology. Series A, Biological sciences and medical sciences.