Lipopolysaccharide-induced tumor necrosis factor-alpha release is controlled by the central nervous system.
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)-alpha within 30 min, which declined by 60% by 120 min. To test our hypothesis that such a rapid increase of TNF-alpha would be either neurally or hormonally controlled, the effect on TNF-alpha 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-alpha was measured by immunoassay.


RESULTS
Among all the drugs tested, only propranolol increased plasma TNF-alpha. Anesthesia significantly blunted the LPS-induced TNF-alpha peak by 50%. Isoproterenol, a beta-adrenergic agonist, also blocked LPS-induced TNF-alpha release by 70% at 30 min and 90% at 120 min. On the contrary, propranolol, a beta-receptor blocker, induced a highly significant 3-fold increase in plasma TNF-alpha concentrations at 30 min and augmented the response to LPS 2-fold after endotoxin injection. Phentolamine, an alpha-receptor blocker, decreased the LPS-induced TNF-alpha release by 57% at 30 min. Similarly, alpha-bromoergocryptine, a dopamine D2 receptor agonist, decreased the LPS-induced TNF-alpha peak by 70% at 30 min and 50% at 120 min.


CONCLUSIONS
We conclude that TNF-alpha is at least in part neurally controlled since the anesthetic blocked its response to LPS. The fact that isoproterenol decreased the LPS-induced TNF-alpha release, whereas propranolol augmented basal and LPS-induced release suggests that the sympathetic nervous system inhibits basal and LPS-stimulated TNF-alpha release via beta-adrenergic receptors. Since phentolamine blocked LPS-induced release, this release may be induced, in part at least, by LPS-stimulated adrenergic drive acting on alpha-adrenergic receptors. The suppressive action of bromoergocryptine, a dopamine D2 receptor agonist, on LPS-induced TNF-alpha release may be mediated in part by suppression of prolactin release, which triggers TNF-alpha release.
Mastronardi
C A
CA
Pennington Biomedical Research Center, Lousiana State University, Baton Rouge, LA 70808-4124, USA.
Yu
W H
WH
McCann
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S
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000777:Anesthetics / Q000494:pharmacology; D000818:Animals; D001971:Bromocriptine / Q000494:pharmacology; D002395:Catecholamines / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D002490:Central Nervous System / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D015213:Neuroimmunomodulation / Q000187:drug effects* / Q000502:physiology; D010646:Phentolamine / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017983:Receptors, Catecholamine / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism
D000317:Adrenergic alpha-Antagonists; D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D000777:Anesthetics; D002395:Catecholamines; D018491:Dopamine Agonists; D008070:Lipopolysaccharides; D017983:Receptors, Catecholamine; D014409:Tumor Necrosis Factor-alpha; D001971:Bromocriptine; D011433:Propranolol; D007545:Isoproterenol; D010646:Phentolamine