Serotonin 5-Hydroxytryptamine2A Receptor Activation Suppresses Tumor Necrosis Factor-α-Induced Inflammation with Extraordinary Potency

Abstract

The G protein-coupled serotonin 5-hydroxytryptamine (5-HT) 2A receptor is primarily recognized for its role in brain neurotransmission, where it mediates a wide variety of functions, including certain aspects of cognition. However, there is significant expression of this receptor in peripheral tissues, where its importance is largely unknown. We have now discovered that activation of 5-HT 2A receptors in primary aortic smooth muscle cells provides a previously unknown and extremely potent inhibition of tumor necrosis factor (TNF)-␣-mediated inflammation. 5-HT 2A receptor stimulation with the agonist (R)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane [(R)-DOI] rapidly inhibits a variety of TNF-␣-mediated proinflammatory markers, including intracellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule 1 (VCAM-1), and interleukin (IL)-6 gene expression, nitric-oxide synthase activity, and nuclear translocation of nuclear factor B, with IC 50 values of only 10 to 20 pM.It is significant that proinflammatory markers can also be inhibited by (R)-DOI hours after treatment with TNF-␣. With the exception of a few natural toxins, no current drugs or small molecule therapeutics demonstrate a comparable potency for any physiological effect. TNF-␣-mediated inflammatory pathways have been strongly implicated in a number of diseases, including atherosclerosis, rheumatoid arthritis, psoriasis, type II diabetes, depression, schizophrenia, and Alzheimer's disease. Our results indicate that activation of 5-HT 2A receptors represents a novel, and extraordinarily potent, potential therapeutic avenue for the treatment of disorders involving TNF-␣-mediated inflammation. Note that because (R)-DOI can significantly inhibit the effects of TNF-␣ many hours after the administration of TNF-␣, potential therapies could be aimed not only at preventing inflammation but also treating inflammatory injury that has already occurred or is ongoing.Serotonin, 5-hydroxytryptamine (5-HT), is a small monoamine molecule primarily known for its role as a neurotransmitter. Within the brain, it modulates a variety of behaviors including cognition, mood, aggression, mating, feeding, and sleep . These behaviors are mediated through interactions at seven different receptor families (5-HT 1-7 ) comprised of 14 distinct subtypes . Each of these are G protein-coupled receptors, with the exception of the 5-HT 3 receptor, which is a ligandgated ion channel. Of all the serotonin receptors, the 5-HT 2A receptor, which is known to primarily couple to the G␣q effector pathway (Roth et al., 1986), has been the one most closely linked to complex behaviors. There is a high level of expression within the frontal cortex, with significant localization to the apical dendrites of cortical pyramidal cells (Willins et al., 1997), and further expression at lower levels PKC, protein kinase C; Gö 6976, 5,6,7,pyrrolo [3,4-c]carbazole-12-propanenitrile; PMA, phorbol 12-myristate 13-acetate; F-22, fragment 6 -22; LA-SS-Az, (2ЈS,4ЈS)-(ϩ)-9,10-didehydro-6-methylergoli...

Evidence for interaction between 5-hydroxytryptamine (serotonin) receptor 2A and MHC type II molecules in the development of rheumatoid arthritis

“…34 However, evidence for the involvement of the serotonin system in inflammation is increasing. [13][14][15] Notably, RA is negatively correlated with schizophrenia. 35 Partition of RA into ACPA-positive and ACPA-negative subtypes is adequate, as more evidence points toward the fact that these two subtypes differ in etiology and pathophysiology.…”

“…11,13 It has been demonstrated that the inhibition of production of TNF-a, an important proinflammatory cytokine, by 5-HT is mediated by 5-HT2A in PBMCs 14 and that the activation of 5-HT2A suppresses TNF-a-induced inflammation in primary aortic smooth muscle cells. 15 Previously we have demonstrated that genetic variations in HTR2A are in association with RA. 16 However, as the strength of the association was moderate, we hypothesized that the strongest genetic risk factor for RA, HLA-DRB1 SE alleles, may modulate it and we can colocalize both products in rheumatoid tissue or in related cells.…”

Circulating tumour necrosis factor is highly correlated with brainstem serotonin transporter availability in humans

“…In other words, central serotonin can have an effect on circulating inflammatory markers. For example, 5HT2A receptor activation has been known to suppress TNF-α induced inflammation with extraordinary potency (Yu et al, 2008). In addition, anecdotal evidence suggest that antidepressants that increase serotonergic neurotransmission have antiinflammatory and analgesic effects.…”

Coronary artery disease and depression: Possible role of brain-derived neurotrophic factor and serotonin transporter gene polymorphisms

“…A polymorphism within the 5-htt 5' upstream region (5-HTTLPR) has been reported, the majority of which is composed of either 14 (S) or 16 (L) repetitive elements. In humans, although infrequent, 18 and 20 repetitive elements (XL) are also present (18)(19)(20)(21). An in vitro transcriptional assay has indicated that the activity of the human 5-htt promoter is regulated by these polymorphic repetitive elements, resulting in differences in the efficacy of 5-HTT reuptake among the allelic variants (22).…”