Effects of serotonin and serotonergic agonists and antagonists on the production of tumor necrosis factor α and interleukin-6

Serotonin (5-HT) is a neurotransmitter and immune modulator. The effect of 5-HT on the production of cytokines by human macrophages and lymphocytes is poorly recognized. In the present article we examine the role of 5-HT in modulating the production of two pro-inflammatory cytokines, i.e. interleukin-6 (IL-6) and tumor necrosis factor-α (TNFα), as well as the role of 5-HT_1A and 5-HT₂ receptors in this process. The specific aims were to examine the effects of 5-HT, p-chlorophenylalanine (PCPA), a 5-HT depleting agent, flesinoxan, a 5-HT_1A agonist, m- chlorophenylpiperazine (mCPP), a 5-HT_2B/2C agonist, and ritanserin, a 5-HT_2A/2C antagonist, on the production of the above cytokines. We found that: (1) 5-HT, 15 μg/ml, significantly decreased IL-6 and TNFα production; (2) pCPA, 5 μM, significantly suppressed the production of IL-6 and TNFα; and (3) mCPP, 2.7 μg/ml, significantly increased the production of IL-6 and TNFα. It is concluded that intracellular 5-HT is necessary for optimal synthesis of IL-6 and TNFα; 5-HT in physiological concentrations may increase IL-6 and TNFα production by stimulating 5-HT₂ receptors; and extracellular 5-HT concentrations above the baseline physiological levels may suppress the production of the above cytokines.