Effect of serotonin on murine macrophages: Suppression of Ia expression by serotonin and its reversal by 5-HT₂ serotonergic receptor antagonists

Serotonin (5-HT), a mediator released from platelets at sites of inflammation, suppressed IFN-γ-induced Ia expression in mouse bone marrow macrophages maintained in vitro. (Mean percent suppression = 63.9% ± 9.2, n = 40). This suppression was not toxic or endotoxin-related, was concentration-dependent, and occurred at the physiologic concentration of 5-HT present at inflammatory sites. The concentration of 5-HT producing the half-maximal effect was 2.5 to 5.5 x 10^-8 M. Related compounds, dopamine, histamine, and tryptamine, were much less potent in suppressing IFN-γ-induced Ia, with maximally suppressing concentrations more than 100-fold higher than the maximally suppressing 5-HT concentration. L-5-hydroxytryptophan (5-HTP), the most potent analog tested, was 10-fold less potent than 5-HT in suppressing Ia expression. The concentration of 5-HTP producing the half-maximal effect = 4 x 10^-7 M. 5-HT suppression of IFN-γ-induced Ia expression was antagonized by the 5-HT₂ type receptor antagonists spiperone, ketanserin, and LY53857. Concentrations of these agents resulting in 50% inhibition of the serotonin effect were 1.5 x 10^-8 M, 7.5 x 10^-8 M, and 4.5 x 10^-12 M, respectively. 5-HT was most effective in suppressing IFN-γ-induced Ia when added early in culture simultaneously with IFN-γ. These data provide functional evidence that 5-HT suppression of IFN-γ-induced Ia expression is mediated through a 5-HT receptor with some characteristics of the 5-HT₂ type. 5-HT may play a physiologic role at sites of inflammation as a modulator of the effects of IFN-γ on macrophage function.