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)-1β and tumor necrosis factor (TNF)-α in response to an in vivo challenge with bacterial lipopolysaccharide in rats. Fenfluramine (2.5-10 mg/kg) suppressed tumor necrosis factor-αproduction, but only fenfluramine (5 and 10 mg/kg) suppressed interleukin-1β production. Fenfluramine (10 mg/kg)-induced suppression of interleukin-1β and tumor necrosis factor-α 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-1β and tumor necrosis factor-α 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-αproduction cannot be accounted for by increased interleukin-10 production, as pretreatment with the β-adrenoceptor antagonist nadolol completely blocked the increase in interleukin-10 without altering the suppression of tumor necrosis factor-α 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-α induced by fenfluramine.