INDOMETHACIN MODULATES CIRCULATING CYTOKINE RESPONSES TO STRENUOUS EXERCISE IN HUMANS

doi:10.1006/cyto.2002.1954

Cytokine

Volume 19, Issue 3, August 2002, Pages 153-158

https://doi.org/10.1006/cyto.2002.1954 Get rights and content

Abstract

Physical stress is associated with circulating cytokinemia. However the mechanisms of cytokine regulation during such stress are not clearly defined. Non-steroidal anti-inflammatory drugs (NSAIDs), including indomethacin, are widely used in countering the effects of excessive exercise, but their impact on circulating pro- and anti-inflammatory cytokine production in healthy humans also remains unclear. This study investigated the effect of five days of oral indomethacin treatment (75 mg per day) on the serum concentrations of IL-6, IL-10, IL-12, and TNF-α induced by exercising healthy volunteers. The results demonstrate that indomethacin does not alter resting serum cytokine concentrations. Increased circulating levels were noted, however, for all four cytokines with exercise, but with a different time-course. During and after strenuous physical exercise, indomethacin treatment blunted serum IL-6, and augmented TNF-α and IL-10. These findings may have important implications for both host defense and the injuries associated with excessively vigorous exercise.

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Moreover, supplementation with different antioxidants alleviates the increase in systemic IL-6 in response to exercise in human contracting skeletal muscle (Fischer et al., 2004). In a similar way, the administration of anti-inflammatory drugs, which inhibit NF-κB activity, diminish the exercise induced increase of IL-6, supporting that NF-κB may represent the possible link between contractile activity and IL-6 synthesis (Kopp and Ghosh, 1994; Rhind et al., 2002). The underpinning mechanisms of age-associated chronic inflammation and frailty remain elusive.
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It is likely that the large variation in the CK response between volunteers also contributed to the lack of ability to detect a significant change since, while there was overall a mean increase in CK levels by 24 h post-ECC in all treatment groups, this was not statistically significant, suggesting a lack of statistical power to detect any significant changes. The lack of any effect of ECC on plasma TNFα, might have been due to the relatively short duration of the exercise protocol employed, since the majority of studies reporting elevations in TNFα concentrations have employed longer duration exercise interventions (i.e. >2 h) to induce muscle damage.7 However, the initial development of muscle soreness, and its persistence throughout the study period in all volunteers, including those who consumed the hydrolysate, suggests that some level of muscle damage and/or inflammation may have been present in all treatment groups, but this did not manifest in changes in circulating markers of inflammation or muscle damage within the timeframe of the protocol.
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Psychosocial stress might increase the risk of atherothrombotic events by setting off an elevation in circulating levels of the proinflammatory cytokine interleukin (IL)-6. We investigated the effect of aspirin and propranolol on the responsiveness of plasma IL-6 levels to acute psychosocial stress. For 5 days, 64 healthy subjects were randomized, double-blind, to daily oral aspirin 100 mg plus long-acting propranolol 80 mg, aspirin 100 mg plus placebo, long-acting propranolol 80 mg plus placebo, or placebo plus placebo. Thereafter, all subjects underwent the 13-min Trier Social Stress Test, which combines a preparation phase, a job interview, and a mental arithmetic task. Plasma IL-6 levels were measured in blood samples collected immediately pre- and post-stress, and 45 min and 105 min thereafter. The change in IL-6 from pre-stress to 105 min post-stress differed between subjects with aspirin medication and those without (p = 0.033; $η_{p}^{2}$ = 0.059). IL-6 levels increased less from pre-stress to 105 min post-stress (p < 0.027) and were lower (p = 0.010) at 105 min post-stress in subjects with aspirin than in subjects without aspirin. The significance of these results was maintained when controlling for gender, age, waist-to-hip ratio, mean arterial blood pressure, and smoking status. Medication with propranolol was not significantly associated with the stress-induced change in IL-6 levels. Also, aspirin and propranolol did not significantly interact in determining the IL-6 stress response. Aspirin but not propranolol attenuated the stress-induced increase in plasma IL-6 levels. This suggests one mechanism by which aspirin treatment might reduce the risk of atherothrombotic events triggered by acute mental stress.
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^f2: Present address: Faculty of Physical Education & Recreation Studies, University of Manitoba, R3N 0V1, Canada

^f1: Correspondence to: Pang N. Shek, Ph.D. Operational Medicine Section, DRDC–Toronto (formerly DCIEM), 1133 Sheppard Avenue West, Toronto, Ontario, M3M 3B9, Canada

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Short CommunicationsINDOMETHACIN MODULATES CIRCULATING CYTOKINE RESPONSES TO STRENUOUS EXERCISE IN HUMANS

Abstract

Biochem Biophys Res Commun

Immunol Today

Baillieres Best Pract Res Clin Endocrinol Metab

Semin Arthritis Rheum

Cytokine

J Biol Chem

Cytokine

Nurs Clin North Am

Cytokine

Gastroenterology

Biochem Pharmacol

Int J Immunopharmacol

Pharmacol Res

Immunopharmacology

Cytokine

Am J Med

Effect of brief maximal exercise on circulating levels of interleukin-12

Eur J Appl Physiol

Inhibition of murine natural killer cell activity by prostaglandins

J Immunol

Are similar inflammatory factors involved in strenuous exercise and sepsis?

Intensive Care Med

Inflammatory cytokines in nonpathological states

News Physiol Sci

In vitro production of IL 1 beta, IL 1 alpha, TNF and IL2 in healthy subjects: distribution, effect of cyclooxygenase inhibition and evidence of independent gene regulation

Eur J Immunol

Oral aspirin and ibuprofen increase cytokine-induced synthesis of IL-1 beta and of tumour necrosis factor-alpha ex vivo

Immunol

Circulating levels of peripheral blood leucocytes and cytokines following competitive cycling

Can J Appl Physiol

Inhibitory effects of anti-inflammatory drugs on interleukin-6 bioactivity

Biol Pharm Bull

Cytokine production ex vivo: effect of raised body temperature

Int J Hyperthermia

Inhibition by cyclo-oxygenase inhibitors of interleukin-6 production by human peripheral blood mononuclear cells

Int J Immunopharmacol

Inhibition of NF-kappa B by sodium salicylate and aspirin

Science

Effect of indomethacin on selected immune parameters in different age groups of mice

Physiol Res

Short Communications
INDOMETHACIN MODULATES CIRCULATING CYTOKINE RESPONSES TO STRENUOUS EXERCISE IN HUMANS