Fenfluramine-induced immunosuppression: an in vivo analysis.
We examined the immunomodulatory potential of acute fenfluramine administration, by measuring production of the pro-inflammatory cytokines interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha in response to an in vivo challenge with bacterial lipopolysaccharide in rats. Fenfluramine (2.5-10 mg/kg) suppressed tumor necrosis factor-alpha production, but only fenfluramine (5 and 10 mg/kg) suppressed interleukin-1beta production. Fenfluramine (10 mg/kg)-induced suppression of interleukin-1beta and tumor necrosis factor-alpha production persisted for 6 and 24 h, respectively. Using in vitro analyses, we demonstrated that the immunosuppressive effect of fenfluramine was not due to a direct effect on immune cells. As fenfluramine activates the hypothalamic pituitary adrenal axis, we examined the ability of the glucocorticoid receptor antagonist mifepristone to block fenfluramine-induced immunosuppression. However, mifepristone (10 mg/kg) failed to attenuate the suppressive effect of fenfluramine on interleukin-1beta and tumor necrosis factor-alpha production, indicating that glucocorticoids do not mediate fenfluramine-induced immunosuppression. We also assessed the effect of fenfluramine on production of the anti-inflammatory cytokine interleukin-10, as interleukin-10 can suppresses pro-inflammatory cytokine production. Fenfluramine (10 mg/kg) increased interleukin-10 production following an in vivo lipopolysaccharide challenge. However, the ability of fenfluramine to suppress tumor necrosis factor-alpha production cannot be accounted for by increased interleukin-10 production, as pretreatment with the beta-adrenoceptor antagonist nadolol completely blocked the increase in interleukin-10 without altering the suppression of tumor necrosis factor-alpha induced by fenfluramine. Taken together, these data demonstrate that fenfluramine promotes an immunosuppressive cytokine phenotype in vivo. The suppression of pro-inflammatory cytokines is not due to a direct effect the drug on immune cells, and also occurs independently of glucocorticoid receptor activation. In addition, whilst fenfluramine increases production of the anti-inflammatory cytokine interleukin-10, this cannot account for the suppression of the pro-inflammatory cytokine tumor necrosis factor-alpha induced by fenfluramine.
Connor
Thomas J
TJ
Department of Pharmacology, National University of Ireland, Galway, Ireland. connort@tcd.ie
Kelly
John P
JP
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D003345:Corticosterone / Q000097:blood; D016207:Cytokines / Q000096:biosynthesis / Q000097:blood / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005277:Fenfluramine / Q000494:pharmacology*; D006727:Hormone Antagonists / Q000494:pharmacology; D007165:Immunosuppression Therapy; D007375:Interleukin-1 / Q000096:biosynthesis / Q000097:blood; D016753:Interleukin-10 / Q000096:biosynthesis / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D015735:Mifepristone / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018490:Serotonin Agents / Q000494:pharmacology*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000319:Adrenergic beta-Antagonists; D016207:Cytokines; D006727:Hormone Antagonists; D007375:Interleukin-1; D008070:Lipopolysaccharides; D018490:Serotonin Agents; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D005277:Fenfluramine; D015735:Mifepristone; D003345:Corticosterone