Lipopolysaccharide-Induced Tumor Necrosis Factor-Alpha Release Is Controlled by the Central Nervous System

Abstract

Objective: Lipopolysaccharide (LPS) injection in mammals orchestrates the release of many proinflammatory and anti-inflammatory cytokines. Intravenous administration of 0.2 mg/kg of LPS into unanesthetized rats with indwelling jugular catheters provoked a rapid, 50-fold increase in plasma tumor necrosis factor (TNF)-α within 30 min, which declined by 60% by 120 min. To test our hypothesis that such a rapid increase of TNF-α would be either neurally or hormonally controlled, the effect on TNF-α release of anesthesia (ketamine/acepromazine/xylazine) and catecholaminergic agonists and antagonists, either alone or in the presence of LPS, was determined. Methods: Rats bearing indwelling external jugular catheters were injected with the test drug or saline after removal of 0.6 ml of blood (–10 min). At time zero, LPS or saline was administered. Thereafter, blood samples were drawn at 15, 30, 120, 240 and 360 min. TNF-α was measured by immunoassay. Results: Among all the drugs tested, only propranolol increased plasma TNF-α. Anesthesia significantly blunted the LPS-induced TNF-α peak by 50%. Isoproterenol, a β-adrenergic agonist, also blocked LPS-induced TNF-α release by 70% at 30 min and 90% at 120 min. On the contrary, propranolol, a β-receptor blocker, induced a highly significant 3-fold increase in plasma TNF-α concentrations at 30 min and augmented the response to LPS 2-fold after endotoxin injection. Phentolamine, an α-receptor blocker, decreased the LPS-induced TNF-α release by 57% at 30 min. Similarly, α-bromoergocryptine, a dopamine D2 receptor agonist, decreased the LPS-induced TNF-α peak by 70% at 30 min and 50% at 120 min. Conclusions: We conclude that TNF-α is at least in part neurally controlled since the anesthetic blocked its response to LPS. The fact that isoproterenol decreased the LPS-induced TNF-α release, whereas propranolol augmented basal and LPS-induced release suggests that the sympathetic nervous system inhibits basal and LPS-stimulated TNF-α release via β-adrenergic receptors. Since phentolamine blocked LPS-induced release, this release may be induced, in part at least, by LPS-stimulated adrenergic drive acting on α-adrenergic receptors. The suppressive action of bromoergocryptine, a dopamine D2 receptor agonist, on LPS-induced TNF-α release may be mediated in part by suppression of prolactin release, which triggers TNF-α release.