Serotonin mediates PGE2 overexpression through 5-HT2A and 5-HT3 receptor subtypes in serum-free tissue culture of macrophage-like synovial cells.
Serotonin antagonists show impressive analgesic efficacy in rheumatoid arthritis, osteoarthritis (OA) or fibromyalgia; however, this effect is not well understood. We examined the mechanism of serotonin-induced inflammation and its antagonists in OA. Serotonin receptor subtypes and COX-2 were analysed by RT-PCR from synovial tissue. Serum-free cultures were stimulated with 10 muM serotonin and/or the antagonists ketanserin (5-HT(2A)), tropisetron (5-HT(3)) and parecoxib (COX-2). Prostaglandin E(2) (PGE(2)), tumour necrosis factor alpha (TNF-alpha), interleukin 1beta (IL-1beta) and leukotriene B4 (LTB4) were measured by an immunoassay in the supernatants. RT-PCR results showed mRNA for 5-HT(2A) and 5-HT(3) receptors, and COX-2. PGE(2) in the supernatants increased by 261.2% +/- 56.7 (mean +/- SEM; P = 0.007) in response to serotonin. TNF-alpha, IL-1beta and LTB4 levels did not change. Ketanserin, tropisetron and parecoxib suppressed PGE(2). The serotonin-induced PGE(2) overexpression appeared thus to be mediated by 5-HT(2A) and 5-HT(3) receptors. This activation might involve COX-2. The findings may explain the potent benefit of 5-HT(3) antagonists.
Seidel
Matthias F
MF
Rheumatology, Medizinische Universitäts-Poliklink, Bonn, Germany. Matthias.Seidel@ukb.uni-bonn.de
Fiebich
Bernd L
BL
Ulrich-Merzenich
Gudrun
G
Candelario-Jalil
Eduardo
E
Koch
Franz-Walter
FW
Vetter
Hans
H
D000368:Aged; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism*; D004347:Drug Interactions; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D053583:Interleukin-1beta / Q000378:metabolism; D007555:Isoxazoles / Q000494:pharmacology; D007650:Ketanserin / Q000494:pharmacology; D007975:Leukotriene B4 / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D008875:Middle Aged; D010003:Osteoarthritis / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D012333:RNA, Messenger / Q000378:metabolism; D044402:Receptor, Serotonin, 5-HT2A / Q000235:genetics* / Q000378:metabolism; D044406:Receptors, Serotonin, 5-HT3 / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012701:Serotonin / Q000494:pharmacology*; D018490:Serotonin Agents / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D013583:Synovial Membrane / Q000166:cytology*; D000077526:Tropisetron; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016895:Culture Media, Serum-Free; D016861:Cyclooxygenase Inhibitors; D007211:Indoles; D053583:Interleukin-1beta; D007555:Isoxazoles; D012333:RNA, Messenger; D044402:Receptor, Serotonin, 5-HT2A; D044406:Receptors, Serotonin, 5-HT3; D018490:Serotonin Agents; D012702:Serotonin Antagonists; D014409:Tumor Necrosis Factor-alpha; D007975:Leukotriene B4; D012701:Serotonin; D000077526:Tropisetron; D007650:Ketanserin; C409945:parecoxib; D051546:Cyclooxygenase 2; D015232:Dinoprostone