Serotonin mediates PGE2 overexpression through 5-HT2A and 5-HT3 receptor subtypes in serum-free tissue culture of macrophage-like synovial cells

Abstract

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.

The effects of 5HT3 receptor antagonist granisetron on inflammatory parameters and angiogenesis in the air-pouch model of inflammation

“…Activated macrophages appear to be the major cellular characters capable of elevating angiogenesis by virtue of their secretory products [42]. In the present model, which tries to mimic chronic inflammatory and wound-healing processes, a cascade of inflammatory events is triggered after induction of inflammation by carrageenan and culminates in new blood vessel formation [43,45]. Here, we show that angiogenesis development was progressive and comparable with the inflammatory cell accumulation in rat pouches.…”

“…Nevertheless, little is known about receptor-mediated signals that are involved in the biological activity of TNFα during inflammatory angiogenesis and especially, in the model of air-pouch angiogenesis. More recently Seidel et al suggested that the inflammation might be triggered by stimulation of 5HT 3 receptor subtypes with consecutive overexpression of PGE 2 [42] and it is well known that PGE 2 regulate angiogenesis in inflammatory granulation tissue [43][44][45][46][47]. Also it has been reported that the production of TNFα is inhibited in immune cells by serotonin [30,[48][49][50], and serotonin-stimulated PGE 2 release inhibits TNFα release [51,52].…”

Neuromediators in inflammation—a macrophage/nerve connection

“…This was associated with reduced eosinophil recruitment and a concomitant drop in Th2 cytokines, corroborating the idea that 5-HT is a chemoattractant for eosinophils (Boehme et al, 2004). Elevated 5-HT levels were also observed in other Th2 conditions such as murine atopic dermatitis (Soga et al, 2007) or DSS-induced colitis (Ghia et al, 2009b), while in Th1-driven rheumatoid arthritis, 5-HT enhanced the synthesis of prostaglandin E2 (Seidel et al, 2008).…”

The anti-inflammatory effects of the 5-HT3 receptor antagonist tropisetron are mediated by the inhibition of p38 MAPK activation in primary human monocytes

“…e l s e v i e r . c o m / l o c a t e / i n t i m p inflammatory pain [11][12][13][14] as well as chemically induced pain [15,16] responded well to 5-HT 3 receptor antagonists, probably because the latter inhibit nociceptor stimulation.…”