Serotonin increases interleukin-6 synthesis in human vascular smooth muscle cells

Background-Interleukin-6 (IL-6) is a key molecule in chronic inflammation a nd has been implicated in the progression of atherosclerosis. Serotonin (5- hydroxytryptamine; 5-HT) causes vascular contraction and proliferation, but its role in atherogenesis has not been clarified. We investigated the effe cts of 5-HT on IL-6 synthesis in human vascular smooth muscle cells (VSMCs) . Methods and Results-IL-6 levels in the culture medium of VSMCs were determi ned by ELISA. IL-6 mRNA accumulation was determined by use of a Quantikine mRNA colorimetric quantification kit. NF-kappaB activation was tested by ge l retardation assay. 5-HT induced IL-6 production by VSMCs in a time- and d ose-dependent manner, with increased IL-6 mRNA accumulation and nuclear fac tor-kappaB activation. The effect of 5-HT on IL-6 production was significan tly inhibited by the 5-HT2 receptor antagonist ketanserin and the selective 5-HT2A receptor antagonist sarpogrelate. Conversely, the 5-HT2 receptor ag onist alpha -methyl-5-HT increased IL-6 production. The protein kinase C (P KC) inhibitor calphostin C, but not the protein kinase A inhibitor KT5720, suppressed 5-HT-induced IL-6 production. The effect of 5-HT was also abolis hed in PKC-depleted VSMCs after pretreatment with phorbol 13-myristate 13-a cetate for 24 hours. Conclusions-5-HT acts on 5-HT2A receptors and increases IL-6 synthesis in h uman VSMCs at least partially through a PKC-dependent pathway. These result s suggested that 5-HT may contribute to inflammatory activation of the vess els during atherogenesis.