We studied in 10 healthy subjects the effect of chronic enteral supplementation of antioxidants (vitamins E, C, A, allopurinol, and N-acetylcysteine) on cytokine production by monocytes at rest, end exercise (60-min cycling at 60% of maximum oxygen consumption), and 60 min post-exercise (recovery). The percentage and the mean fluorescent intensity (MFI) of both unstimulated and lipopolysaccharide (LPS)-stimulated tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6–producing monocytes were detected using flow cytometry. Antioxidants decreased the percentage of unstimulated IL-6–producing monocytes following exercise, while their MFI increased at rest. The percentage of LPS-stimulated monocytes increased after exercise and they produced more IL-6 both at rest and following exercise. The percentage of unstimulated and LPS-stimulated IL-1β–producing monocytes was not affected by antioxidants. The MFI of IL-1β–produced unstimulated monocytes was increased after antioxidants both at rest and following exercise. After antioxidants, LPS-stimulated monocytes produced more IL-1β following exercise. Antioxidants decreased the percentage of TNF-α spontaneously-produced monocytes following exercise, which produced more TNF-α at recovery. Antioxidants did not affect the percentage of LPS-stimulated monocytes producing TNF-α, while LPS-stimulated production of TNF-α increased both at rest and following exercise. Antioxidants differentially affect TNF-α, IL-1β, and IL-6 production by monocytes, with a general tendency of augmenting cytokine production.
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References
1.
AlessioHM, GoldfarbAH, CaoG. 1997. Exercise-induced oxidative stress before and after vitamin C supplementation. Int J Sport Nutr, 7:1–9.
2.
AliMH, SchlidtSA, ChandelNS, HynesKL, SchumackerPT, GewertzBL. 1999. Endothelial permeability and IL-6 production during hypoxia: role of ROS in signal transduction. Am J Physiol, 277:L1057–L1065.
3.
BergmanM, SalmanH, DjaldettiM, FishL, PunskyI, BesslerH. 2004. In vitro immune response of human peripheral blood cells to vitamins C and E. J Nutr Biochem, 15:45–50.
4.
BogdanC, PaikJ, VodovotzY, NathanC. 1992. Contrasting mechanisms for suppression of macrophage cytokine release by transforming growth factor-beta and interleukin-10. J Biol Chem, 267:23301–23308.
5.
BruunsgaardH, PoulsenHE, PedersenBK, NyyssonenK, KaikkonenJ, SalonenJT. 2003. Long-term combined supplementations with alpha-tocopherol and vitamin C have no detectable anti-inflammatory effects in healthy men. J Nutr, 133:1170–1173.
6.
DevarajS, JialalI. 2000. Alpha tocopherol supplementation decreases serum C-reactive protein and monocyte interleukin-6 levels in normal volunteers and type 2 diabetic patients. Free Radic Biol Med, 29:790–792.
7.
DevarajS, JialalI. 2005. Alpha-tocopherol decreases tumor necrosis factor-alpha mRNA and protein from activated human monocytes by inhibition of 5-lipoxygenase. Free Radic Biol Med, 38:1212–1220.
8.
DevarajS, LiD, JialalI. 1996. The effects of alpha tocopherol supplementation on monocyte function. Decreased lipid oxidation, interleukin 1 beta secretion, and monocyte adhesion to endothelium. J Clin Invest, 98:756–763.
9.
DrenthJP, KrebbersRJ, BijzetJ, van der MeerJW. 1998. Increased circulating cytokine receptors and ex vivo interleukin-1 receptor antagonist and interleukin-1beta production but decreased tumour necrosis factor-alpha production after a 5-km run. Eur J Clin Invest, 28:866–872.
10.
ErridgeC, KennedyS, SpickettCM, WebbDJ. 2008. Oxidized phospholipid inhibition of toll-like receptor (TLR) signaling is restricted to TLR2 and TLR4: roles for CD14, LPS-binding protein, and MD2 as targets for specificity of inhibition. J Biol Chem, 283:24748–24759.
11.
FormanHJ, TorresM. 2002. Reactive oxygen species and cell signaling: respiratory burst in macrophage signaling. Am J Respir Crit Care Med, 166:S4–S8.
12.
GleesonM. 2007. Immune function in sport and exercise. J Appl Physiol, 103:693–699.
13.
GoebelMU, MillsPJ, IrwinMR, ZieglerMG. 2000. Interleukin-6 and tumor necrosis factor-alpha production after acute psychological stress, exercise, and infused isoproterenol: differential effects and pathways. Psychosom Med, 62:591–598.
14.
GuhaM, MackmanN. 2001. LPS induction of gene expression in human monocytes. Cell Signal, 13:85–94.
15.
HaddadJJ, Safieh-GarabedianB, SaadeNE, LandSC. 2001. Thiol regulation of pro-inflammatory cytokines reveals a novel immunopharmacological potential of glutathione in the alveolar epithelium. J Pharmacol Exp Ther, 296:996–1005.
16.
HanssonGK. 2005. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med, 352:1685–1695.
17.
HartelC, StrunkT, BucskyP, SchultzC. 2004. Effects of vitamin C on intracytoplasmic cytokine production in human whole blood monocytes and lymphocytes. Cytokine, 27:101–106.
18.
HartelC, PuzikA, GopelW, TemmingP, BucskyP, SchultzC. 2007. Immunomodulatory effect of vitamin C on intracytoplasmic cytokine production in neonatal cord blood cells. Neonatology, 91:54–60.
19.
HeunksLM, VinaJ, van HerwaardenCL, FolgeringHT, GimenoA, DekhuijzenPN. 1999. Xanthine oxidase is involved in exercise-induced oxidative stress in chronic obstructive pulmonary disease. Am J Physiol, 277:R1697–R1704.
20.
HsuHY, WenMH. 2002. Lipopolysaccharide-mediated reactive oxygen species and signal transduction in the regulation of interleukin-1 gene expression. J Biol Chem, 277:22131–22139.
21.
JammesY, SteinbergJG, BregeonF, DelliauxS. 2004. The oxidative stress in response to routine incremental cycling exercise in healthy sedentary subjects. Respir Physiol Neurobiol, 144:81–90.
22.
JengKC, YangCS, SiuWY, TsaiYS, LiaoWJ, KuoJS. 1996. Supplementation with vitamins C and E enhances cytokine production by peripheral blood mononuclear cells in healthy adults. Am J Clin Nutr, 64:960–965.
23.
JialalI, DevarajS. 2003. Antioxidants and atherosclerosis: don’t throw out the baby with the bath water. Circulation, 107:926–928.
24.
KaulN, DevarajS, GrundySM, JialalI. 2001. Failure to demonstrate a major anti-inflammatory effect with alpha tocopherol supplementation (400 IU/day) in normal subjects. Am J Cardiol, 87:1320–1323.
25.
KaulN, FormanHJ. 1996. Activation of NF kappa B by the respiratory burst of macrophages. Free Radic Biol Med, 21:401–405.
LeeuwenbergJF, DentenerMA, BuurmanWA. 1994. Lipopolysaccharide LPS-mediated soluble TNF receptor release and TNF receptor expression by monocytes. Role of CD14, LPS binding protein, and bactericidal/permeability-increasing protein. J Immunol, 152:5070–5076.
28.
LibbyP. 2002. Inflammation in atherosclerosis. Nature, 420:868–874.
29.
MaJ, ChenT, MandelinJ, CeponisA, MillerNE, HukkanenM, MaGF, KonttinenYT. 2003. Regulation of macrophage activation. Cell Mol Life Sci, 60:2334–2346.
30.
MainoVC, PickerLJ. 1998. Identification of functional subsets by flow cytometry: intracellular detection of cytokine expression. Cytometry, 34:207–215.
31.
McArdleF, PattwellDM, VasilakiA, McArdleA, JacksonMJ. 2005. Intracellular generation of reactive oxygen species by contracting skeletal muscle cells. Free Radic Biol Med, 39:651–657.
32.
MeydaniSN, BarklundMP, LiuS, MeydaniM, MillerRA, CannonJG, MorrowFD, RocklinR, BlumbergJB. 1990. Vitamin E supplementation enhances cell-mediated immunity in healthy elderly subjects. Am J Clin Nutr, 52:557–563.
33.
MillerYI, ChangMK, BinderCJ, ShawPX, WitztumJL. 2003. Oxidized low density lipoprotein and innate immune receptors. Curr Opin Lipidol, 14:437–445.
34.
NdengeleMM, MuscoliC, WangZQ, DoyleTM, MatuschakGM, SalveminiD. 2005. Superoxide potentiates NF-kappaB activation and modulates endotoxin-induced cytokine production in alveolar macrophages. Shock, 23:186–193.
35.
PedersenBK, Hoffman-GoetzL. 2000. Exercise and the immune system: regulation, integration, and adaptation. Physiol Rev, 80:1055–1081.
36.
SmithJK, DykesR, DouglasJE, KrishnaswamyG, BerkS. 1999. Long-term exercise and atherogenic activity of blood mononuclear cells in persons at risk of developing ischemic heart disease. JAMA, 281:1722–1727.
37.
van FurthR. 1998. Human monocytes and cytokines. Res Immunol, 149:719–720.
38.
van TitsLJ, DemackerPN, de GraafJ, Hak-LemmersHL, StalenhoefAF. 2000. alpha-tocopherol supplementation decreases production of superoxide and cytokines by leukocytes ex vivo in both normolipidemic and hypertriglyceridemic individuals. Am J Clin Nutr, 71:458–464.
39.
VassilakopoulosT, KaratzaMH, KatsaounouP, KollintzaA, ZakynthinosS, RoussosC. 2003. Antioxidants attenuate the plasma cytokine response to exercise in humans. J Appl Physiol, 94:1025–1032.
40.
Vega-LopezS, KaulN, DevarajS, CaiRY, GermanB, JialalI. 2004. Supplementation with omega3 polyunsaturated fatty acids and all-rac alpha-tocopherol alone and in combination failed to exert an anti-inflammatory effect in human volunteers. Metabolism, 53:236–240.
41.
VirtamoJ, RapolaJM, RipattiS, HeinonenOP, TaylorPR, AlbanesD, HuttunenJK. 1998. Effect of vitamin E and beta carotene on the incidence of primary nonfatal myocardial infarction and fatal coronary heart disease. Arch Intern Med, 158:668–675.
42.
VivekananthanDP, PennMS, SappSK, HsuA, TopolEJ. 2003. Use of antioxidant vitamins for the prevention of cardiovascular disease: meta-analysis of randomised trials. Lancet, 361:2017–2023.
43.
WangX, AllenC, BallowM. 2007. Retinoic acid enhances the production of IL-10 while reducing the synthesis of IL-12 and TNF-alpha from LPS-stimulated monocytes/macrophages. J Clin Immunol, 27:193–200.
44.
WillersonJT, RidkerPM. 2004. Inflammation as a cardiovascular risk factor. Circulation, 109:II2–II10.
45.
YoshidaY, MaruyamaM, FujitaT, AraiN, HayashiR, ArayaJ, MatsuiS, YamashitaN, SugiyamaE, KobayashiM. 1999. Reactive oxygen intermediates stimulate interleukin-6 production in human bronchial epithelial cells. Am J Physiol, 276:L900–L908.
46.
YusufS, DagenaisG, PogueJ, BoschJ, SleightP. 2000. Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med, 342:154–160.
