title: Inflammation and exercise: Inhibition of monocytic intracellular TNF production by acute exercise via β2-adrenergic activation.
abstract: Regular exercise is shown to exert anti-inflammatory effects, yet the effects of acute exercise on cellular inflammatory responses and its mechanisms remain unclear. We tested the hypothesis that sympathoadrenergic activation during a single bout of exercise has a suppressive effect on monocytic cytokine production mediated by β2adrenergic receptors (AR). We investigated the effects of 20-min moderate (65-70% VO2peak) exercise-induced catecholamine production on LPS-stimulated TNF production by monocytes in 47 healthy volunteers and determined AR subtypes involved. We also examined the effects of β-agonist isoproterenol and endogenous β- and α-agonists epinephrine and norepinephrine, and receptor-subtype-specific β- and α-antagonists on TNF production in a series of in vitro investigations. LPS-stimulated TNF production by peripheral blood monocytes was determined intracellularly by flow cytometry, using an intracellular protein transport inhibitor. Percent TNF-producing monocytes and per-cell TNF production with and without LPS was suppressed by exercise with moderate to large effects, which was reversed by a β2-AR antagonist in spite that plasma TNF levels did not change. This inhibitory response in TNF production by exercise was mirrored by β-AR agonists in an agonist-specific and dose-dependent manner in vitro: similar isoproterenol (EC50=2.1-4.7×10-10M) and epinephrine (EC50=4.4-10×10-10M) potency and higher norepinephrine concentrations (EC50=2.6-4.3×10-8M) needed for the effects. Importantly, epinephrine levels observed during acute exercise in vivo significantly inhibited TNF production in vitro. The inhibitory effect of the AR agonists was abolished by β2-, but not by β1- or α-AR blockers. We conclude that the downregulation of monocytic TNF production during acute exercise is mediated by elevated epinephrine levels through β2-ARs. Decreased inflammatory responses during acute exercise may protect against chronic conditions with low-grade inflammation.
authors.affiliation: Department of Psychiatry, University of California, San Diego, USA.
authors.forename: Stoyan
authors.initials: S
authors.lastname: Dimitrov
authors.affiliation: Department of Psychiatry, University of California, San Diego, USA.
authors.forename: Elaine
authors.initials: E
authors.lastname: Hulteng
authors.affiliation: Department of Psychiatry, University of California, San Diego, USA. Electronic address: suzihong@ucsd.edu.
authors.forename: Suzi
authors.initials: S
authors.lastname: Hong
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000328:Adult; D016207:Cytokines / Q000378:metabolism; D004837:Epinephrine / Q000494:pharmacology; D015444:Exercise / Q000502:physiology*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D009638:Norepinephrine / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000097:blood*
chemical_list: D000316:Adrenergic alpha-Agonists; D000318:Adrenergic beta-Agonists; D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D007545:Isoproterenol; D009638:Norepinephrine; D004837:Epinephrine
keywords: Adrenergic agonist; Beta blocker; Cytokine regulation; Exercise; Sympathetic activation