| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 School of Sport and Exercise Sciences
2 Department of Immunology, The Medical School, University of Birmingham, Birmingham, UK
3 GlaxoSmithKline Consumer Healthcare
4 School of Sport and Exercise Sciences, Loughborough University, Loughborough, UK
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
(Received 13 December 2004;
accepted after revision 15 January 2005;
first published online 20 January 2005)
Corresponding author G. Lancaster: RMIT University, School of Medical Sciences, Division of Biosciences, Bundoora Campus, PO Box 71, Bundoora 3083, Victoria, Australia. Email: graeme.lancaster{at}rmit.edu.au
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Despite tremendous advances in our understanding of the role of TLRs in host defence, and the specific signalling events initiated following TLR activation (Beutler, 2004), factors that regulate TLR expression and function are poorly understood. Cytokines exert considerable influence over the development of host immunity, and recently they have been shown to modulate the expression and activation of TLRs. For example, viral infection of human macrophages induces expression of TLR1, TLR2, TLR3 and TLR7 mRNA, a process that has been shown to be dependent upon the production of type 1 interferons (Miettinen et al. 2001), and recent data provide evidence for a differential regulation of TLR expression and activation by type 1 and type 2 cytokines (Krutzik et al. 2003).
Neuroendocrine hormones have a well-established role in modulating the immune system, and recent studies suggest a role for glucocorticoids (GCs) in regulating TLR expression, since dexamethasone (DEX), a synthetic glucocorticoid, was shown to induce TLR2 mRNA expression in epithelial cells (Imasato et al. 2002; Shuto et al. 2002). Furthermore, TLR2 and TLR4 gene expression in peripheral blood mononuclear cells (PBMCs) is enhanced by DEX treatment (Galon et al. 2002). In addition, given that GCs are potent modulators of NF-
B transcriptional activity, and that the activation of NF-B is required for an increase in the expression of several TLR-controlled genes, it is likely that GCs play an important role in modulating TLR function in vivo.
In the present study, we have investigated the regulation of TLR expression and function under physiological conditions in vivo. Firstly, we have examined whether TLR expression and function is subject to circadian timing. Numerous physiological processes display circadian timing and, importantly, circadian variations in the endogenous circulating GC concentration influence many aspects of the immune system (Angeli et al. 1992; Dhabhar et al. 1994; Petrovsky & Harrison, 1997). Preliminary data suggest that TLR expression is influenced by GCs (Galon et al. 2002; Imasato et al. 2002); furthermore, the activation of NF-B, a transcription factor critical to the induction of TLR responsive genes, is also inhibited by GCs. Therefore, we hypothesized that TLR expression and function would display circadian timing.
Secondly, we have examined the influence of 1.5 h of strenuous exercise in hot (34°C) environmental conditions on TLR expression and function. Strenuous exercise is known to influence numerous aspects of the immune system (Pedersen & Hoffman-Goetz, 2000), and an exercise-induced increase in the circulating concentration of several immunomodulatory hormones is believed to be central to the modulation of the immune system by exercise. We hypothesized that exercise would influence the expression and function of TLRs, possibly via increases in the circulating concentrations of stress hormones. To augment the exercise-induced stress hormone response, and thus maximize the likelihood of observing an effect of exercise on TLR expression and function, exercise in combination with heat stress was employed.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
To examine whether TLR expression and activation was influenced by circadian rhythmicity, peripheral venous blood samples were obtained from eight (five males, three females) healthy volunteers (age 25 ± 1 years, body mass 68 ± 3 kg) at 07.00 h after an overnight fast and again at 17.00 h following a 3–4 h fast. To examine the effects of strenuous exercise on TLR expression and activation, 11 healthy, moderate-to-well endurance-trained males (age 25 ± 1 years, body mass 74 ± 2 kg, maximal oxygen uptake 
; means ±
S.E.M.) volunteered to participate in the study. All participants were nonsmokers, were not taking any medication, and had remained free of respiratory infection for 4 weeks prior to participation in the study. Subjects were informed as to the purposes and risks of the experiments before voluntarily giving their written and informed consent. The study was approved by the University of Birmingham Ethics Committee and conformed to the Declaration of Helsinki.
Exercise protocol
At least 7 days prior to the experimental trial, each subject's maximal work rate (Wmax) was determined during an incremental exercise test to volitional exhaustion, as previously described (Jentjens et al. 2002). In addition, subjects completed a familiarization exercise trial at 55%
Wmax for 1.5 h at 34°C. Subjects were instructed to abstain from alcohol, tobacco and exercise on the day prior to the experimental trials. On the day of the experimental trial, subjects reported to the Human Performance Laboratory at the University of Birmingham after an overnight fast. To avoid circadian rhythms in immunomodulatory hormones, all trials commenced at 07.00 h. An indwelling catheter was inserted into an antecubital vein of one arm, and a resting blood sample was drawn (Rest). Following 5 min of exercise at 40%
Wmax, subjects commenced the 1.5 h of cycling exercise at 55%
Wmax (
65%
). Further blood samples were obtained upon completion of the exercise (Post-exercise), and following 2 h of resting recovery (2 h Post-exercise). Subjects consumed a total of 1.5 l of flavoured water during the experimental trials. Furthermore, all trials were performed in the heat (34°C room temperature, 30% relative humidity).
At each time point during the experimental trials, whole blood (6 ml) was collected in sterile K3EDTA vacutainer tubes (Becton Dickinson, Oxford, UK). From this, total and differential leucocyte counts were determined, while the remainder was separated immediately by centrifugation (1500 g) for 10 min, and aliquots of plasma were stored at –20°C until analysis for adrenocorticotropic hormone (ACTH), cortisol, growth hormone and glucose. In addition, whole blood (7 ml) was collected in sterile lithium-heparin vacutainer tubes (Becton Dickinson, Oxford, UK), and kept at room temperature until the end of the trial for analysis of TLR expression and activation.
Determination of TLR expression
To determine cell surface expression of TLRs on circulating monocytes and neutrophils, whole blood was surface stained with CD14-FITC (Becton Dickinson Biosciences) and antihuman PE-conjugated TLR1 (clone GD2.F4), TLR2 (clone TL2.1) or TLR4 (clone HTA 125) (e-Bioscience), or the appropriate isotype control for TLR1 (mouse IgG1-PE), TLR2 (mouse IgG2a-PE) and TLR4 (mouse IgG2a-PE) (e-Bioscience). In contrast to the cell surface localization of TLR1, 2 and 4, TLR9 is localized intracellularly. Therefore, following surface staining with CD14-FITC, samples were permeabilized and stained with antihuman TLR9-PE (clone eB72-1665) or rat IgG2a isotype control antibodies (e-Bioscience). Samples were analysed on a flow cytometer (BD FACSCalibur) equipped with the CellQuest software package (BD Biosciences). Cells were gated according to side-scatter and CD14-FITC expression, and the change in the geometric mean fluorescence intensity (GMFI) between TLR1, 2, 4 and 9 antibodies and isotype controls was obtained to quantify TLR expression.
Assessment of IL-6 production following stimulation with TLR ligands
Whole blood (3 x 106 leucocytes ml–1) was added to RPMI 1640 medium supplemented with 2 mM L-glutamine, 100 U ml–1 penicillin and 100 µg ml–1 streptomycin. In addition, Brefeldin A (10 µg ml–1), a potent inhibitor of intracellular protein transport, was added to all samples. Samples were then stimulated with either 10 µg ml–1 zymosan (a specific TLR2 and 6 ligand) from Saccharomyces cerevisiae, 10 ng ml–1 lipopolysaccharide (LPS; a specific TLR4 ligand) purified from Escherichia coli (011:B4 strain) (InvivoGen), or they were unstimulated. Following incubation at 37°C for 6 h in a 5% CO2 humidified atmosphere, samples were surface stained with CD14-fluorescein isothiocyanate (FITC) (BD Biosciences). After permeabilization, samples were stained using intracellular PE-conjugated antibodies against human IL-6, or mouse IgG1-PE as a negative control. Samples were analysed on a flow cytometer (BD FACSCalibur) equipped with the CellQuest software package (BD Biosciences). Monocytes were gated according to side-scatter and CD14-FITC expression, and the GMFI of the IL-6-PE antibody was obtained to quantify intracellular cytokine expression.
Assessment of costimulatory molecule expression following stimulation with TLR ligands
Whole blood (3 x 106 leucocytes ml–1) was added to RPMI 1640 medium supplemented with 2 mM L-glutamine, 100 U ml–1 penicillin and 100 µg ml–1 streptomycin. Samples were then stimulated with either 10 µg ml–1 zymosan, 10 ng ml–1 LPS, 25 µg ml–1 polyinosine-polycytidylic acid (Poly(I:C)) a synthetic dsRNA analogue (a specific TLR3 ligand) (InvivoGen), or were unstimulated. Following incubation at 37°C for either 6 or 24 h in a 5% CO2 humidified atmosphere, samples were surface stained with CD14-FITC, CD80-PE, HLA-DR-PerCP (BD Biosciences), CD86-PE (Santa Cruz Biotechnology) and appropriate isotype controls. Samples were analysed on a flow cytometer (BD FACSCalibur) equipped with the CellQuest software package (BD Biosciences). Monocytes were gated according to side-scatter and CD14-FITC expression, and the change in the GMFI between CD80-PE, CD86-PE and HLA-DR-PerCP antibodies and isotype controls was obtained to quantify cell surface expression of costimulatory molecules.
Circulating stress hormones and metabolites
Plasma cortisol (DRG Instruments, Germany), growth hormone (DRG Instruments) and ACTH (Biomerica, USA) concentrations were determined by enzyme-linked immunosorbent assay (ELISA). Plasma glucose concentration was determined enzymatically (Randox Laboratories Ltd, UK) on a semiautomatic analyser (COBAS MIRA plus; Roche, Switzerland).
Statistical analysis
A one-way (time) ANOVA was used to compare the means of data obtained from the exercise study. Where the ANOVA revealed a significant F ratio, differences were inspected with Tukey's honestly significant difference post hoc test. A Student's paired samples t test was used to compare the means of data obtained from the diurnal rhythm study. SPSS version 10 for Windows (SPSS, Inc., Chicago, IL, USA) was used to calculate these statistics. The level of statistical significance accepted to reject the null hypothesis was P < 0.05. Data in the text, tables and figures are means ± S.E.M.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The endogenous circulating cortisol concentration typically reaches its daily peak soon after waking in the morning, and its nadir prior to sleep in the evening. Therefore, we obtained peripheral venous blood samples at 07.00 h in the morning (30 min after waking) and 17.00 h in the evening. As expected, we observed a significantly higher circulating cortisol concentration in samples obtained in the morning compared with the evening (morning, 802 ± 92 nmol l–1; evening, 323 ± 44 nmol l–1; means ±
S.E.M., n
= 8, P < 0.001, paired sample t test). We observed no statistically significant differences in the expression of TLR1, 2, 4 or 9 on CD14+ monocytes between samples obtained at 07.00 h (morning) and 17.00 h (evening) (Fig. 1A). Similarly, no differences in the expression of TLR1, 2 or 4 on neutrophils were observed; although there was a statistically significant difference (P < 0.05) between morning and evening samples for TLR9 expression (Fig. 1B). The relative levels of TLR expression we observed, i.e. TLR9 > TLR2 > TLR1 and TLR4, are consistent with previous studies (Renshaw et al. 2002; Marsik et al. 2003).
|
Using flow cytometry, we also determined the intracellular expression (GMFI) of IL-6 in CD14+ monocytes following 6 h of incubation with LPS and zymosan. Interestingly, although IL-6 expression within CD14+ monocytes following zymosan stimulation was higher (P < 0.05) in evening compared with morning samples (consistent with the CD80/86 and MHC class II expression data), intracellular IL-6 expression following LPS stimulation was higher (P < 0.05) in morning compared with evening samples (Fig. 1F). These data indicate a role of physiological alterations in immunomodulatory hormones in the regulation of TLR activation.
The effects of strenuous exercise on TLR expression and activation
To examine whether an acute physiological stressor influences the expression and activation of TLRs, we obtained peripheral blood samples from 11 healthy volunteers before, immediately after, and following 2 h of resting recovery from 90 min of strenuous exercise in the heat (34°C). Compared with values obtained at rest, exercise resulted in a significant decrease in the surface expression of TLR1 (P < 0.005), TLR2 (P < 0.005) and TLR4 (P < 0.005) on CD14+ monocytes; furthermore, this decrease was maintained at 2 h postexercise (Fig. 2A, B and C). No effect of exercise was observed on TLR9 expression (Fig. 2D).
|
|
|
|
|
Exercise resulted in a significant elevation in the circulating concentrations of ACTH and growth hormone (Table 1). Plasma cortisol concentrations were similar in post-exercise samples compared with samples obtained at rest; however, the cortisol concentration was significantly lower in samples obtained at 2 h post-exercise compared with samples obtained at rest and post-exercise (Table 1). Exercise had no significant effect on the plasma glucose concentration (Table 1).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The expression of TLR1, TLR2 and TLR4 on monocytes was markedly reduced in samples obtained immediately after, and following 2 h of resting recovery from 1.5 h of strenuous exercise, in comparison with samples obtained at rest; no effect of exercise on TLR9 expression was observed. In contrast, we observed no diurnal variation in the expression of TLR1, TLR2, TLR4 or TLR9 on monocytes, and no change in the expression of TLR1, TLR2 or TLR4 on neutrophils. It has been demonstrated previously that GCs modulate TLR expression in vitro (Galon et al. 2002). However, in the present study we observed no circadian rhymicity in TLR expression despite large changes in the endogenous cortisol concentration, and a significant decrease in TLR expression following strenuous exercise despite only a moderate change in circulating cortisol concentrations. Taken together, these data suggest that GCs do not play a major role in regulating TLR expression under physiological conditions in vivo. While exercise, surgery (Dybdahl et al. 2002), endotoxaemia (Marsik et al. 2003) and ageing (Renshaw et al. 2002) have all been associated with changes in TLR expression, the factors responsible are unclear, and while our data provide evidence against a role for GCs in regulating TLR expression, a variety of factors are known to regulate TLR expression. In particular, several cytokines have been shown to regulate the expression of TLRs in vitro (Staege et al. 2000; Miettinen et al. 2001; Krutzik et al. 2003), and increases in the concentrations of specific cytokines have been associated with changes in TLR expression in vivo in human disease conditions (Krutzik et al. 2003; Seibl et al. 2003). Interestingly, exercise induces a large and sustained increase in the circulating concentration of several cytokines (Febbraio & Pedersen, 2002), and it is possible that changes in the circulating cytokine environment may contribute to alterations in the expression of TLRs following exercise.
The upregulation of the accessory signals CD80, CD86 and MHC class II following TLR activation is critical to the generation of adaptive immune responses. Here, we have found that the upregulation of the costimulatory molecules CD80 and CD86 and the antigen-presenting molecule MHC class II on CD14+ monocytes following treatment with a variety of TLR ligands was significantly greater in samples obtained in the evening compared with the morning. Furthermore, the upregulation of CD80, CD86 and MHC class II expression on CD14+ monocytes following TLR activation was significantly lower in samples obtained immediately after, and following 2 h of resting recovery from 1.5 h of strenuous exercise, in comparison with samples obtained at rest. Importantly, NF-B activation is required for the upregulation of CD80, CD86 and MHC class II expression (Yoshimura et al. 2001), and GCs potently negatively regulate NF-B activity (Almawi et al. 2002). Although correlative, our data, which demonstrate diurnal rhymicity in the upregulation of CD80, CD86 and MHC class II expression, provide evidence that GCs modulate TLR function under physiological conditions in vivo. Interestingly, we observed a significant decrease in the upregulation of CD80, CD86 and MHC class II molecules following TLR activation, despite only modest changes in the circulating cortisol concentration. These data strongly suggest that exercise-induced alterations in the circulating cortisol concentration are not responsible for the suppression in TLR function that we observed following exercise. Given that prolonged strenuous exercise results in a marked elevation in the circulation concentration of several cytokines, and that cytokines have been shown to have potent effects on monocyte TLR function in vitro (Krutzik et al. 2003), the exercise-induced alteration in the cytokine environment represents a potential mechanism by which exercise may affect TLR function.
In addition to its well-characterized role in the development of the inflammatory response, it was recently shown that IL-6 production following activation of TLRs is critical to the development of adaptive immune responses (Pasare & Medzhitov, 2003). Similar to the effects of exercise on the upregulation of CD80, CD86 and MHC class II expression, LPS-stimulated monocyte intracellular IL-6 expression was significantly lower in samples obtained immediately after, and following 2 h of resting recovery from 1.5 h of strenuous exercise in comparison with samples obtained at rest. However, intracellular IL-6 expression following zymosan treatment was significantly higher in samples obtained following exercise compared with samples obtained at rest. Given that DEX treatment at physiological levels causes suppression in both LPS- and zymosan-stimulated monocyte intracellular IL-6 production in vitro (G.I. Lancaster, Q. Khan, P. Drysdale, F. Wallace, A.E. Jeukendrup, M.T. Drayson & M. Gleeson, unpublished observations), these data argue against a role for exercise-induced elevations in the circulating cortisol concentration in the modulation of monocyte IL-6 production following exercise. Elucidation of the factors responsible for this differential effect of exercise on monocyte IL-6 production awaits further research.
In human blood, two monocyte populations have been identified, the CD14++CD16–HLA-DR+ classical monocytes and the CD14+CD16+HLA-DR++ pro-inflammatory monocytes (Ziegler-Heitbrock, 1996). It could be argued that the effects we observed of diurnal rhythmicity and exercise on TLR expression and function are due to the differential mobilization of monocyte subsets to the circulation. Indeed the CD14+CD16+ pro-inflammatory monocytes have a higher surface expression of TLR2, and produce a greater amount of tumour necrosis factor (TNF)-
following treatment with LPS or Pam3Cys (TLR2 ligand) compared with the CD14+CD16– classical monocytes (Belge et al. 2002). However, CD14+CD16+ monocytes are mobilized to the circulation to a greater extent than CD14+CD16– monocytes during exercise (Steppich et al. 2000), indicating that the effects of diurnal rhythmicity and exercise on TLR expression and function that we have observed are not due the mobilization of phenotypically distinct monocyte subsets.
In the present study, we have demonstrated that TLR function displays a diurnal rhythmicity, and that prolonged strenuous exercise causes suppression of both TLR expression and function. Our data (diurnal rhythm study) provide the first evidence that immunomodulatory hormones may influence TLR function in vivo. Furthermore, our data also demonstrate that strenuous exercise is a potent modulator of TLR expression and function, and, furthermore, that this effect appears to be independent of changes in immunomodulatory hormones. Further studies are required to confirm the possible influences of hormones and cytokines in the modulation of TLR function in vivo. Finally, epidemiological data indicate that individuals engaged in intensive exercise training have an increased susceptibility to upper respiratory tract infections (Peters & Bateman, 1983; Fitzgerald, 1988; Nieman et al. 1990; Peters et al. 1993). It is possible that the exercise-induced suppression in TLR expression and function that we have observed in the present study may provide a mechanistic basis for these observations. Given the crucial roles of the upregulation of costimulatory molecules, and the production of cytokines by APCs following the activation of TLRs, to the generation of adaptive immune responses (Schnare et al. 2001), future work will be required to examine the clinical importance of changes in TLR expression and function to the generation of in vivo immune responses.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Alexopoulou L, Thomas V, Schnare M, Lobet Y, Anguita J, Schoen RT, Medzhitov R, Fikrig E & Flavell RA (2002). Hyporesponsiveness to vaccination with Borrelia burgdorferi OspA in humans and in TLR1- and TLR2-deficient mice. Nat Med 8, 878–884.[Medline]
Aliprantis
AO, Yang
RB, Mark
MR, Suggett
S, Devaux
B, Radolf
JD, Klimpel
GR, Godowski
P
&
Zychlinsky
A (1999). Cell activation and apoptosis by bacterial lipoproteins through toll-like receptor-2. Science
285, 736–739.
Almawi WY, Abou Jaoude MM & Li XC (2002). Transcriptional and post-transcriptional mechanisms of glucocorticoid antiproliferative effects. Hematol Oncol 20, 17–32.[CrossRef][Medline]
Angeli A, Gatti G, Sartori ML & Masera RG (1992). Chronobiological aspects of the neuroendocrine-immune network. Regulation of human natural killer (NK) cell activity as a model. Chronobiologia 19, 93–110.[Medline]
Belge
KU, Dayyani
F, Horelt
A, Siedlar
M, Frankenberger
M, Frankenberger
B, Espevik
T
&
Ziegler-Heitbrock
L (2002). The proinflammatory CD14+CD16+DR++ monocytes are a major source of TNF. J Immunol
168, 3536–3542.
Beutler B (2004). Inferences, questions and possibilities in Toll-like receptor signalling. Nature 430, 257–263.[CrossRef][Medline]
Dhabhar FS, Miller AH, Stein M, McEwen BS & Spencer RL (1994). Diurnal and acute stress-induced changes in distribution of peripheral blood leukocyte subpopulations. Brain Behav Immun 8, 66–79.[CrossRef][Medline]
Dybdahl
B, Wahba
A, Lien
E, Flo
TH, Waage
A, Qureshi
N, Sellevold
OF, Espevik
T
&
Sundan
A (2002). Inflammatory response after open-heart surgery: release of heat-shock protein 70 and signaling through toll-like receptor-4. Circulation
105, 685–690.
Febbraio
MA
&
Pedersen
BK (2002). Muscle-derived interleukin-6: mechanisms for activation and possible biological roles. FASEB J
16, 1335–1347.
Fitzgerald L (1988). Exercise and the immune system. Immunol Today 9, 337–339.[CrossRef][Medline]
Galon
J, Franchimont
D, Hiroi
N, Frey
G, Boettner
A, Ehrhart-Bornstein
M, O'Shea
JJ, Chrousos
GP
&
Bornstein
SR (2002). Gene profiling reveals unknown enhancing and suppressive actions of glucocorticoids on immune cells. FASEB J
16, 61–71.
Hayashi F, Smith KD, Ozinsky A, Hawn TR, Yi EC, Goodlett DR, Eng JK, Akira S, Underhill DM & Aderem A (2001). The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 410, 1099–1103.[CrossRef][Medline]
Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, Sanjo H, Matsumoto M, Hoshino K, Wagner H, Takeda K & Akira S (2000). A Toll-like receptor recognizes bacterial DNA. Nature 408, 740–745.[CrossRef][Medline]
Imasato
A, Desbois-Mouthon
C, Han
J, Kai
H, Cato
AC, Akira
S
&
Li
JD (2002). Inhibition of p38 MAPK by glucocorticoids via induction of MAPK phosphatase-1 enhances nontypeable Haemophilus influenzae-induced expression of toll-like receptor 2. J Biol Chem
277, 47444–47450.
Janeway CA Jr & Medzhitov R (2002). Innate immune recognition. Annu Rev Immunol 20, 197–216.[CrossRef][Medline]
Jentjens
RL, Wagenmakers
AJ
&
Jeukendrup
AE (2002). Heat stress increases muscle glycogen use but reduces the oxidation of ingested carbohydrates during exercise. J Appl Physiol
92, 1562–1572.
Krutzik SR, Ochoa MT, Sieling PA, Uematsu S, Ng YW, Legaspi A, Liu PT, Cole ST, Godowski PJ, Maeda Y, Sarno EN, Norgard MV, Brennan PJ, Akira S, Rea TH & Modlin RL (2003). Activation and regulation of Toll-like receptors 2 and 1 in human leprosy. Nat Med 9, 525–532.[CrossRef][Medline]
Lemaitre B, Nicolas E, Michaut L, Reichhart JM & Hoffmann JA (1996). The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86, 973–983.[CrossRef][Medline]
Marsik C, Mayr F, Cardona F, Derhaschnig U, Wagner OF & Jilma B (2003). Endotoxaemia modulates Toll-like receptors on leucocytes in humans. Br J Haematol 121, 653–656.[CrossRef][Medline]
Medzhitov R (2001). Toll-like receptors and innate immunity. Nat Rev Immunol 1, 135–145.[CrossRef][Medline]
Medzhitov R, Preston-Hurlburt P & Janeway CA Jr (1997). A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388, 394–397.[CrossRef][Medline]
Miettinen M, Sareneva T, Julkunen I & Matikainen S (2001). IFNs activate toll-like receptor gene expression in viral infections. Genes Immun 2, 349–355.[CrossRef][Medline]
Nieman DC, Johanssen LM, Lee JW & Arabatzis K (1990). Infectious episodes in runners before and after the Los Angeles Marathon. J Sports Med Phys Fitness 30, 316–328.[Medline]
Pasare
C
&
Medzhitov
R (2003). Toll pathway-dependent blockade of CD4+CD25+ T-cell-mediated suppression by dendritic cells. Science
299, 1033–1036.
Pedersen
BK
&
Hoffman-Goetz
L (2000). Exercise and the immune system: regulation, integration, and adaptation. Physiol Rev
80, 1055–1081.
Peters EM & Bateman ED (1983). Ultramarathon running and upper respiratory tract infections. An epidemiological survey. S Afr Med J 64, 582–584.[Medline]
Peters
EM, Goetzsche
JM, Grobbelaar
B
&
Noakes
TD (1993). Vitamin C supplementation reduces the incidence of postrace symptoms of upper-respiratory-tract infection in ultramarathon runners. Am J Clin Nutr
57, 170–174.
Petrovsky N & Harrison LC (1997). Diurnal rhythmicity of human cytokine production: a dynamic disequilibrium in T helper cell type 1/T helper cell type 2 balance? J Immunol 158, 5163–5168.[Abstract]
Renshaw
M, Rockwell
J, Engleman
C, Gewirtz
A, Katz
J
&
Sambhara
S (2002). Cutting edge: impaired Toll-like receptor expression and function in aging. J Immunol
169, 4697–4701.
Scanga
CA, Aliberti
J, Jankovic
D, Tilloy
F, Bennouna
S, Denkers
EY, Medzhitov
R
&
Sher
A (2002). Cutting edge: MyD88 is required for resistance to Toxoplasma gondii infection and regulates parasite-induced IL-12 production by dendritic cells. J Immunol
168, 5997–6001.
Schnare M, Barton GM, Holt AC, Takeda K, Akira S & Medzhitov R (2001). Toll-like receptors control activation of adaptive immune responses. Nat Immunol 2, 947–950.[CrossRef][Medline]
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.
Seki
E, Tsutsui
H, Tsuji
NM, Hayashi
N, Adachi
K, Nakano
H, Futatsugi-Yumikura
S, Takeuchi
O, Hoshino
K, Akira
S, Fujimoto
J
&
Nakanishi
K (2002). Critical roles of myeloid differentiation factor 88-dependent proinflammatory cytokine release in early phase clearance of Listeria monocytogenes in mice. J Immunol
169, 3863–3868.
Shuto
T, Imasato
A, Jono
H, Sakai
A, Xu
H, Watanabe
T, Rixter
DD, Kai
H, Andalibi
A, Linthicum
F, Guan
YL, Han
J, Cato
AC, Lim
DJ, Akira
S
&
Li
JD (2002). Glucocorticoids synergistically enhance nontypeable Haemophilus influenzae-induced Toll-like receptor 2 expression via a negative cross-talk with p38 MAP kinase. J Biol Chem
277, 17263–17270.
Staege H, Schaffner A & Schneemann M (2000). Human toll-like receptors 2 and 4 are targets for deactivation of mononuclear phagocytes by interleukin-4. Immunol Lett 71, 1–3.[CrossRef][Medline]
Steppich
B, Dayyani
F, Gruber
R, Lorenz
R, Mack
M
&
Ziegler-Heitbrock
HW (2000). Selective mobilization of CD14+ CD16+ monocytes by exercise. Am J Physiol Cell Physiol
279, C578–586.
Takeda K, Kaisho T & Akira S (2003). Toll-like receptors. Annu Rev Immunol 21, 335–376.[CrossRef][Medline]
Takeuchi
O, Hoshino
K
&
Akira
S (2000). Cutting edge: TLR2-deficient and MyD88-deficient mice are highly susceptible to Staphylococcus aureus infection. J Immunol
165, 5392–5396.
Thoma-Uszynski
S, Stenger
S, Takeuchi
O, Ochoa
MT, Engele
M, Sieling
PA, Barnes
PF, Rollinghoff
M, Bolcskei
PL, Wagner
M, Akira
S, Norgard
MV, Belisle
JT, Godowski
PJ, Bloom
BR
&
Modlin
RL (2001). Induction of direct antimicrobial activity through mammalian toll-like receptors. Science
291, 1544–1547.
Yamamoto M, Sato S, Hemmi H, Sanjo H, Uematsu S, Kaisho T, Hoshino K, Takeuchi O, Kobayashi M, Fujita T, Takeda K & Akira S (2002). Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4. Nature 420, 324–329.[CrossRef][Medline]
Yoshimura S, Bondeson J, Brennan FM, Foxwell BM & Feldmann M (2001). Role of NFkappaB in antigen presentation and development of regulatory T cells elucidated by treatment of dendritic cells with the proteasome inhibitor PSI. Eur J Immunol 31, 1883–1893.[CrossRef][Medline]
Ziegler-Heitbrock HW (1996). Heterogeneity of human blood monocytes: the CD14+CD16+ subpopulation. Immunol Today 17, 424–428.[CrossRef][Medline]
|
Acknowledgements |
|---|
Author's present address
G. Lancaster: RMIT University, School of Medical Sciences, Division of Biosciences, Bundoora Campus, PO Box 71, Bundoora 3083, Victoria, Australia.
This article has been cited by other articles:
|
|
 |
|
  C. T. Ranjith-Kumar, K. E. Duffy, J. L. Jordan, A. Eaton-Bassiri, R. Vaughan, S. A. Hoose, R. J. Lamb, R. T. Sarisky, and C. C. Kao Single-Stranded Oligonucleotides Can Inhibit Cytokine Production Induced by Human Toll-Like Receptor 3 Mol. Cell. Biol., July 15, 2008; 28(14): 4507 - 4519. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. R. Pauli, E. R. Ropelle, D. E. Cintra, M. A. Carvalho-Filho, J. C. Moraes, C. T. De Souza, L. A. Velloso, J. B. C. Carvalheira, and M. J. A. Saad Acute physical exercise reverses S-nitrosation of the insulin receptor, insulin receptor substrate 1 and protein kinase B/Akt in diet-induced obese Wistar rats J. Physiol., January 15, 2008; 586(2): 659 - 671. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Gleeson Immune function in sport and exercise J Appl Physiol, August 1, 2007; 103(2): 693 - 699. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M. Cooper, S. Radom-Aizik, C. Schwindt, and F. Zaldivar Jr. Dangerous exercise: lessons learned from dysregulated inflammatory responses to physical activity J Appl Physiol, August 1, 2007; 103(2): 700 - 709. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Febbraio Exercise and inflammation J Appl Physiol, July 1, 2007; 103(1): 376 - 377. [Full Text] [PDF]
|
|
|
|
 |
|
 C. T. Ranjith-Kumar, W. Miller, J. Sun, J. Xiong, J. Santos, I. Yarbrough, R. J. Lamb, J. Mills, K. E. Duffy, S. Hoose, et al. Effects of Single Nucleotide Polymorphisms on Toll-like Receptor 3 Activity and Expression in Cultured Cells J. Biol. Chem., June 15, 2007; 282(24): 17696 - 17705. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. T. Ranjith-Kumar, W. Miller, J. Xiong, W. K. Russell, R. Lamb, J. Santos, K. E. Duffy, L. Cleveland, M. Park, K. Bhardwaj, et al. Biochemical and Functional Analyses of the Human Toll-like Receptor 3 Ectodomain J. Biol. Chem., March 9, 2007; 282(10): 7668 - 7678. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Statistically significant difference (P < 0.005) from pre-exercise. GMFI, geometric mean fluorescence intensity.
