Skip to main content

Advertisement

Log in

Role of Toll-like receptor 2 and 4 signaling pathways on the inflammatory response to resistance training in elderly subjects

  • Published:
AGE Aims and scope Submit manuscript

A Correction to this article was published on 08 December 2023

This article has been updated

Abstract

This study assessed the effects of a resistance exercise training program on the inflammatory response associated with Toll-like receptor (TLR) 2 and TLR4 signaling pathways in senior participants. Twenty-six healthy subjects (age, 69.5 ± 1.3) were randomized to a training (TG; n = 16) or a control (CG; n = 10) group. TG performed an 8-week resistance training program, while CG followed their daily routines. Peripheral blood mononuclear cells were isolated from blood samples obtained before and after the intervention, and levels of proteins involved in the TLR2, TLR4, and myeloid differentiation primary response gene 88 (MyD88)-dependent and MyD88-independent pathways were analyzed. The inflammatory status was evaluated through messenger RNA (mRNA) and protein content of interleukin (IL)-10 and tumor necrosis factor alpha (TNF-α) and plasma levels of C-reactive protein (CRP). After the 8-week resistance training, TLR2 and TLR4 protein expression was reduced in TG. MyD88, p65, phospho-p38, TIR domain-containing adaptor inducing interferon (TRIF), IKKi/IKKε, phospho-interferon regulatory factor (IRF) 3, and phosho-IRF7 were also downregulated in TG after the intervention. The training program induced an increase of phospho-extracellular signal-regulated kinases 1 and 2 (ERK1/2) and Hsp70 and a reduction of Hsp60. While TNF-α mRNA and protein values remained unchanged in both TG and CG, IL-10 mRNA and protein content were upregulated in TG after the intervention. CRP values decreased in TG only. The increase in Hsp70 negatively correlated with TLR2 and TLR4 downregulation. These data suggest that resistance exercise may represent an effective tool to ameliorate the pro-inflammatory status of old participants through an attenuation of MyD88-dependent and MyD88-independent TLR2 and TLR4 signaling pathways.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Change history

References

  • Akira S, Sato S (2003) Toll-like receptors and their signaling mechanisms. Scand J Infect Dis 35:555–562

    Article  CAS  PubMed  Google Scholar 

  • Asea A, Rehli M, Kabingu E, Boch JA, Bare O, Auron PE, Stevenson MA, Calderwood SK (2002) Novel signal transduction pathway utilized by extracellular HSP70: role of toll-like receptor (TLR) 2 and TLR4. J Biol Chem 277:15028–15034

    Article  CAS  PubMed  Google Scholar 

  • Beg AA (2002) Endogenous ligands of toll-like receptors: implications for regulating inflammatory and immune responses. Trends Immunol 23:509–512

    Article  CAS  PubMed  Google Scholar 

  • Beharka AA, Meydani M, Wu D, Leka LS, Meydani A, Meydani SN (2001) Interleukin-6 production does not increase with age. J Gerontol A Biol Sci Med Sci 56:B81–B88

    Article  CAS  PubMed  Google Scholar 

  • Bruunsgaard H (2002) Effects of tumor necrosis factor-alpha and interleukin-6 in elderly populations. Eur Cytokine Netw 13:389–391

    CAS  PubMed  Google Scholar 

  • Colbert LH, Visser M, Simonsick EM, Tracy RP, Newman AB, Kritchevsky SB, Pahor M, Taaffe DR, Brach J, Rubin S, Harris TB (2004) Physical activity, exercise, and inflammatory markers in older adults: findings from the health, aging and body composition study. J Am Geriatr Soc 52:1098–1104

    Article  PubMed  Google Scholar 

  • Coll RC, O’Neill LA (2010) New insights into the regulation of signalling by toll-like receptors and nod-like receptors. J Innate Immun 2:406–421

    Article  CAS  PubMed  Google Scholar 

  • Connolly DJ, O’Neill LA (2012) New developments in toll-like receptor targeted therapeutics. Curr Opin Pharmacol 12:510–518

    Article  CAS  PubMed  Google Scholar 

  • Cristofaro P, Opal SM (2006) Role of toll-like receptors in infection and immunity: clinical implications. Drugs 66:15–29

    Article  CAS  PubMed  Google Scholar 

  • Cuevas MJ, Almar M, García-Glez JC, García-López D, De Paz JA, Alvear-Ordenes I, González-Gallego J (2005) Changes in oxidative stress markers and NF-kappaB activation induced by sprint exercise. Free Radic Res 39:431–439

    Article  CAS  PubMed  Google Scholar 

  • De la Fuente M, Miquel J (2009) An update of the oxidation-inflammation theory of aging: the involvement of the immune system in oxi-inflamm-aging. Curr Pharm Des 15:3003–3026

    Article  PubMed  Google Scholar 

  • De AK, Kodys KM, Yeh BS, Miller-Graziano C (2000) Exaggerated human monocyte IL-10 concomitant to minimal TNF-alpha induction by heat-shock protein 27 (Hsp27) suggests Hsp27 is primarily an antiinflammatory stimulus. J Immunol 165:3951–3958

    Article  CAS  PubMed  Google Scholar 

  • Donges CE1, Duffield R, Drinkwater EJ (2010) Effects of resistance or aerobic exercise training on interleukin-6, C-reactive protein, and body composition. Med Sci Sports Exerc 42:304–312

    Article  CAS  PubMed  Google Scholar 

  • Ershler WB, Keller ET (2005) Age-associated increased interleukin-6 gene expression, late-life diseases, and frailty. Annu Rev Med 51:245–270

    Article  Google Scholar 

  • Fagiolo U, Cossarizza A, Scala E, Fanalesbelasio E, Ortolani C, Cozzi E, Monti D, Franceschi C, Paganelli R (1993) Increased cytokine production in mononuclear-cells of healthy elderly people. Eur J Immunol 23:2375–2378

    Article  CAS  PubMed  Google Scholar 

  • Fehrenbach E, Niess AM, Schlotz E, Passek F, Dickhuth HH, Northoff H (2000) Transcriptional and translational regulation of heat shock proteins in leukocytes of endurance runners. J Appl Physiol 89(1985):704–710

    CAS  PubMed  Google Scholar 

  • Fernandez-Gonzalo R, De Paz JA, Rodriguez-Miguelez P, Cuevas MJ, González-Gallego J (2012) Effects of eccentric exercise on toll-like receptor 4 signaling pathway in peripheral blood mononuclear cells. J Appl Physiol 112:2011–2018

    Article  CAS  PubMed  Google Scholar 

  • Fernandez-Gonzalo R, De Paz JA, Rodriguez-Miguelez P, Cuevas MJ, González-Gallego J (2014) TLR4-mediated blunting of inflammatory responses to eccentric exercise in young women. Mediators Inflamm doi:10.1155/2014/479395

  • Flynn MG, McFarlin BK, Phillips MD, Stewart LK, Timmerman KL (2003) Toll-like receptor 4 and CD14 mRNA expression are lower in resistive exercise-trained elderly women. J Appl Physiol 95:1833–1842

    CAS  PubMed  Google Scholar 

  • Giannopoulou I, Fernhall B, Carhart R, Weinstock RS, Baynard T, Figueroa A, Kanaley JA (2005) Effects of diet and/or exercise on the adipocytokine and inflammatory cytokine levels of postmenopausal women with type 2 diabetes. Metabolism 54:866–875

    Article  CAS  PubMed  Google Scholar 

  • Gleeson M, McFarlin B, Flynn M (2006) Exercise and toll-like receptors. Exerc Immunol Rev 12:34–53

    PubMed  Google Scholar 

  • González-Gallego J, García-Mediavilla MV, Sánchez-Campos S, Tuñón MJ (2010) Fruit polyphenols, immunity and inflammation. Br J Nutr 104(Suppl 3):S15–S27

    Article  PubMed  Google Scholar 

  • Haigis MC, Yankner BA (2010) The aging stress response. Mol Cell 40:333–344

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hao HN, Zheng B, Nasser S, Ren W, Latteier M, Wooley P, Morawa L (2010) The roles of monocytic heat shock protein 60 and toll-like receptors in the regional inflammation response to wear debris particles. J Biomed Mater Res A 92:1373–1381

    PubMed  Google Scholar 

  • Harris MB, Starnes JW (2001) Effects of body temperature during exercise training on myocardial adaptations. Am J Physiol Heart Circ Physiol 280:H2271–H2280

    CAS  PubMed  Google Scholar 

  • Hofmann SR, Morbach H, Schwarz T, Rosen-Wolff A, Girschick HJ, Hedrich CM (2012) Attenuated TLR4/MAPK signaling in monocytes from patients with CRMO results in impaired IL-10 expression. Clin Immunol 145:69–76

    Article  CAS  PubMed  Google Scholar 

  • Jiang W, Hu M, Rao J, Xu X, Wang X, Kong L (2010) Over-expression of toll-like receptors and their ligands in small-for-size graft. Hepatol Res 40:318–329

    Article  CAS  PubMed  Google Scholar 

  • Jimenez-Jimenez R, Cuevas MJ, Almar M, Lima E, García-López D, De Paz JA, González-Gallego J (2008) Eccentric training impairs NF-kappaB activation and over-expression of inflammation-related genes induced by acute eccentric exercise in the elderly. Mech Ageing Dev 129:313–321

    Article  CAS  PubMed  Google Scholar 

  • Kawai T, Akira S (2006) TLR signaling. Cell Death Differ 13:816–825

    Article  CAS  PubMed  Google Scholar 

  • Keller C, Keller P, Giralt M, Hidalgo J, Pedersen BK (2004) Exercise normalises overexpression of TNF-alpha in knockout mice. Biochem Biophys Res Commun 321:179–182

    Article  CAS  PubMed  Google Scholar 

  • Kilmartin B, Reen DJ (2004) HSP60 induces self-tolerance to repeated HSP60 stimulation and cross-tolerance to other pro-inflammatory stimuli. Eur J Immunol 34:2041–2051

    Article  CAS  PubMed  Google Scholar 

  • Kramer HF, Goodyear LJ (2007) Exercise, MAPK, and NF-kappaB signaling in skeletal muscle. J Appl Physiol 103:388–395

    Article  CAS  PubMed  Google Scholar 

  • Kullo IJ, Khaleghi M, Hensrud DD (2007) Markers of inflammation are inversely associated with VO2 max in asymptomatic men. J Appl Physiol 102:1374–1379

    Article  CAS  PubMed  Google Scholar 

  • Larbi A, Dupuis G, Douziech N, Khalil A, Fulop T (2004) Low-grade inflammation with aging has consequences for T-lymphocyte signaling. signal transduction pathways, chromatin structure, and gene expression mechanisms as therapeutic targets. Ann N Y Acad Sci 1030:125–133

    Article  CAS  PubMed  Google Scholar 

  • Lee JS, Bruce CR, Spurrell BE, Hawley JA (2002) Effect of training on activation of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase pathways in rat soleus muscle. Clin Exp Pharmacol Physiol 29:655–660

    Article  CAS  PubMed  Google Scholar 

  • Lira FS, Rosa JC, Zanchi NE, Yamashita AS, Lopes RD, Lopes AC, Batista ML Jr, Seelaender M (2009) Regulation of inflammation in the adipose tissue in cancer cachexia: effect of exercise. Cell Biochem Funct 27:71–75

    Article  CAS  PubMed  Google Scholar 

  • Locke M, Noble EG, Atkinson BG (1990) Exercising mammals synthesize stress proteins. Am J Physiol 258:C723–C729

    CAS  PubMed  Google Scholar 

  • Martin-Murphy BV, Holt MP, Ju C (2010) The role of damage associated molecular pattern molecules in acetaminophen-induced liver injury in mice. Toxicol Lett 192:387–394

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • McFarlin BK, Flynn MG, Campbell WW, Stewart LK, Timmerman KL (2004) TLR4 is lower in resistance-trained older women and related to inflammatory cytokines. Med Sci Sports Exerc 36:1876–1883

    Article  CAS  PubMed  Google Scholar 

  • McFarlin BK, Flynn MG, Campbell WW, Craig BA, Robinson JP, Stewart LK, Timmerman KL, Coen PM (2006) Physical activity status, but not age, influences inflammatory biomarkers and toll-like receptor 4. J Gerontol A Biol Sci Med Sci 61:388–393

    Article  PubMed  Google Scholar 

  • Miettinen M, Sareneva T, Julkunen I, Matikainen S (2001) IFNs activate toll-like receptor gene expression in viral infections. Genes Immun 2:349–355

    Article  CAS  PubMed  Google Scholar 

  • Milne KJ, Noble EG (2002) Exercise-induced elevation of HSP70 is intensity dependent. J Appl Physiol 93:561–568

    CAS  PubMed  Google Scholar 

  • Moldoveanu AI, Shephard RJ, Shek PN (2001) The cytokine response to physical activity and training. Sports Med 31:115–144

    Article  CAS  PubMed  Google Scholar 

  • Murlasits Z, Cutlip RG, Geronilla KB, Rao KM, Wonderlin WF, Alway SE (2006) Resistance training increases heat shock protein levels in skeletal muscle of young and old rats. Exp Gerontol 41:398–406

    Article  CAS  PubMed  Google Scholar 

  • Neubauer O, Sabapathy S, Lazarus R, Jowett JB, Desbrow B, Peake JM, Cameron-Smith D, Haseler LJ, Wagner KH, Bulmer AC (2013) Transcriptome analysis of neutrophils after endurance exercise reveals novel signaling mechanisms in the immune response to physiological stress. J Appl Physiol 114:1677–1688

    Article  CAS  PubMed  Google Scholar 

  • Nickel T, Hanssen H, Emslander I, Drexel V, Hertel G, Schmidt-Trucksäss A, Summo C, Sisic Z, Lambert M, Hoster E, Halle M, Weis M (2011) Immunomodulatory effects of aerobic training in obesity. Mediators Inflamm. doi:10.1155/2011/308965

    PubMed Central  PubMed  Google Scholar 

  • Nicklas BJ, Hsu FC, Brinkley TJ, Church T, Goodpaster BH, Kritchevsky SB, Pahor M (2008) Exercise training and plasma C-reactive protein and interleukin-6 in elderly people. J Am Geriatr Soc 56:2045–2052

    Article  PubMed Central  PubMed  Google Scholar 

  • Noble EG, Shen GX (2012) Impact of exercise and metabolic disorders on heat shock proteins and vascular inflammation. Autoimmune Dis. doi:10.1155/2012/836519

    PubMed Central  PubMed  Google Scholar 

  • Oberbach A, Tonjes A, Kloting N, Fasshauer M, Kratzsch J, Busse MW, Paschke R, Stumvoll M, Blüher M (2006) Effect of a 4 week physical training program on plasma concentrations of inflammatory markers in patients with abnormal glucose tolerance. Eur J Endocrinol 154:577–585

    Article  CAS  PubMed  Google Scholar 

  • Ohashi K, Burkart V, Flohe S, Kolb H (2000) Cutting edge: heat shock protein 60 is a putative endogenous ligand of the toll-like receptor-4 complex. J Immunol 164:558–561

    Article  CAS  PubMed  Google Scholar 

  • Oshiumi H, Matsumoto M, Funami K, Akazawa T, Seya T (2003) TICAM-1, an adaptor molecule that participates in toll-like receptor 3-mediated interferon-beta induction. Nat Immunol 4:161–167

    Article  CAS  PubMed  Google Scholar 

  • Partridge L (2011) Some highlights of research on aging with invertebrates, 2010. Aging Cell 10:5–9

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Pedersen BK, Saltin B (2006) Evidence for prescribing exercise as therapy in chronic disease. Scand J Med Sci Sports 16(Suppl 1):3–63

    Article  PubMed  Google Scholar 

  • Petersen AM, Pedersen BK (2005) The anti-inflammatory effect of exercise. J Appl Physiol 98:1154–1162

    Article  CAS  PubMed  Google Scholar 

  • Pockley AG, Calderwood SK, Multhoff G (2009) The atheroprotective properties of Hsp70: a role for Hsp70-endothelial interactions? Cell Stress Chaperones 14:545–553

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Samelman TR (2000) Heat shock protein expression is increased in cardiac and skeletal muscles of Fischer 344 rats after endurance training. Exp Physiol 85:92–102

    Article  CAS  PubMed  Google Scholar 

  • Schell MT, Spitzer AL, Johnson JA, Lee D, Harris HW (2005) Heat shock inhibits NF-kB activation in a dose- and time-dependent manner. J Surg Res 129:90–93

    Article  CAS  PubMed  Google Scholar 

  • Schottelius AJ, Mayo MW, Sartor RB, Baldwin AS Jr (1999) Interleukin-10 signaling blocks inhibitor of kappaB kinase activity and nuclear factor kappaB DNA binding. J Biol Chem 274:31868–31874

    Article  CAS  PubMed  Google Scholar 

  • Seibl R, Birchler T, Loeliger S, Hossle JP, Gay RE, Saurenmann T, Michel BA, Seger RA, Gay S, Lauener RP (2003) Expression and regulation of toll-like receptor 2 in rheumatoid arthritis synovium. Am J Pathol 162:1221–1227

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Simar D, Malatesta D, Mas E, Delage M, Caillaud C (2012) Effect of an 8-weeks aerobic training program in elderly on oxidative stress and HSP72 expression in leukocytes during antioxidant supplementation. J Nutr Health Aging 16:155–161

    Article  CAS  PubMed  Google Scholar 

  • Simpson RJ, Lowder TW, Spielmann G, Bigley AB, LaVoy EC, Kunz H (2012) Exercise and the aging immune system. Ageing Res Rev 11:404–420

    Article  CAS  PubMed  Google Scholar 

  • Singh T, Newman AB (2011) Inflammatory markers in population studies of aging. Ageing Res Rev 10:319–329

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Starkie R, Ostrowski SR, Jauffred S, Febbraio M, Pedersen BK (2003) Exercise and IL-6 infusion inhibit endotoxin-induced TNF-alpha production in humans. FASEB J 17:884–886

    CAS  PubMed  Google Scholar 

  • Steensberg A, Fischer CP, Keller C, Moller K, Pedersen BK (2003) IL-6 enhances plasma IL-1ra, IL-10, and cortisol in humans. Am J Physiol Endocrinol Metab 285:E433–E437

    CAS  PubMed  Google Scholar 

  • Stewart LK, Flynn MG, Campbell WW, Craig BA, Robinson JP, McFarlin BK, Timmerman KL, Coen PM, Felker J, Talbert E (2005) Influence of exercise training and age on CD14+ cell-surface expression of toll-like receptor 2 and 4. Brain Behav Immun 19:389–397

    Article  CAS  PubMed  Google Scholar 

  • Stewart LK, Flynn MG, Campbell WW, Craig BA, Robinson JP, Timmerman KL, McFarlin BK, Coen PM, Talbert E (2007) The influence of exercise training on inflammatory cytokines and C-reactive protein. Med Sci Sports Exerc 39:389–397

    Article  Google Scholar 

  • Taylor LW, Wilborn CD, Kreider RB, Willoughby DS (2012) Effects of resistance exercise intensity on extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase activation in men. J Strength Cond Res 26:599–607

    PubMed  Google Scholar 

  • van Ginneken MM, de Graaf-Roelfsema E, Keizer HA, van Dam KG, Wijnberg ID, van der Kolk JH, van Breda E (2006) Effect of exercise on activation of the p38 mitogen-activated protein kinase pathway, c-Jun NH2 terminal kinase, and heat shock protein 27 in equine skeletal muscle. Am J Vet Res 67:837–844

    Article  PubMed  Google Scholar 

  • Veneroso C, Tuñón MJ, González-Gallego J, Collado PS (2009) Melatonin reduces cardiac inflammatory injury induced by acute exercise. J Pineal Res 47:184–191

    Article  CAS  PubMed  Google Scholar 

  • Vieira RP, Claudino RC, Duarte AC, Santos AB, Perini A, Faria Neto HC, Mauad T, Martins MA, Dolhnikoff M, Carvalho CR (2007) Aerobic exercise decreases chronic allergic lung inflammation and airway remodeling in mice. Am J Respir Crit Care Med 176:871–877

    Article  PubMed  Google Scholar 

  • Walsh RC, Koukoulas I, Garnham A, Moseley PL, Hargreaves M, Febbraio MA (2001) Exercise increases serum Hsp72 in humans. Cell Stress Chaperones 6:386–393

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Weber MH, da Rocha RF, Schnorr CE, Schröder R, Moreira JC (2012) Changes in lymphocyte HSP70 levels in women handball players throughout 1 year of training: the role of estrogen levels. J Physiol Biochem 68:365–375

    Article  CAS  PubMed  Google Scholar 

  • Weiss YG, Bromberg Z, Raj N, Raphael J, Goloubinoff P, Ben-Neriah Y, Deutschman CS (2007) Enhanced heat shock protein 70 expression alters proteasomal degradation of IkappaB kinase in experimental acute respiratory distress syndrome. Crit Care Med 35:2128–2138

    Article  CAS  PubMed  Google Scholar 

  • Zbinden-Foncea H, Raymackers JM, Deldicque L, Renard P, Francaux M (2012) TLR2 and TLR4 activate p38 MAPK and JNK during endurance exercise in skeletal muscle. Med Sci Sports Exerc 44:1463–1472

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by Plan Nacional I+D+I DEP2010-17574, Spain.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Javier González-Gallego.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rodriguez-Miguelez, P., Fernandez-Gonzalo, R., Almar, M. et al. Role of Toll-like receptor 2 and 4 signaling pathways on the inflammatory response to resistance training in elderly subjects. AGE 36, 9734 (2014). https://doi.org/10.1007/s11357-014-9734-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11357-014-9734-0

Keywords

Navigation