Abstract
Tumor necrosis factor alpha (TNF-α) plays a key role in inflammation, and its production and signaling contribute to many inflammatory related diseases. Recently, we discovered that selective activation of serotonin 5-HT2A receptors with the agonist (R)-DOI produces a super-potent blockade of proinflammatory markers in primary rat aortic smooth muscle cells. Here, we demonstrate that systemic administration of (R)-DOI can block the systemic effects of TNF-α in whole animal, with potent anti-inflammatory effects in the aortic arch and small intestine. This includes blockade of TNF-α-induced expression of pro-inflammatory cell adhesion (Icam-1, Vcam-1), cytokine (Il-6, IL-1b), and chemokine (Mcp-1, Cx3cl1) genes, and expression of VCAM-1 protein in the intestine. Further, systemic (R)-DOI also prevents the TNF-α-induced increase of circulating IL-6. Importantly, utilizing receptor selective antagonists, we have demonstrated that the mechanism underlying the systemic anti-inflammatory effects of (R)-DOI is activation of serotonin 5-HT2A receptors. Our results highlight a powerful new role for the serotonin 5-HT2A receptor in inflammatory processes, and indicate that agonism of serotonin receptors may represent an effective and novel approach to develop powerful small molecule therapeutics for inflammatory diseases and conditions such as atherosclerosis and inflammatory bowel disease.
Highlights
Serotonin (5 hydroxytryptamine; 5-HT) is a neurotransmitter and hormone whose effects are mediated through interactions at seven different families of receptor proteins, comprised of 14 different subtypes, consisting of 13 G-protein coupled receptors and one ligand-gated ion channel [1]
Results (R)-DOI has Potent Anti-inflammatory Activity in Vivo To explore the effects of systemic serotonin receptor activation on systemic Tumor necrosis factor alpha (TNF-a) mediated inflammation in vivo, we pretreated normal young adult male mice with (R)-DOI (i.p.), followed 30 minutes later by treatment with a low dose of TNF-a (i.p.) that was predicted to produce a moderate systemic inflammatory response
We show here that the primary mechanism for the anti-inflammatory effects of (R)-DOI is through activation of the 5-HT2A receptor
Summary
Serotonin (5 hydroxytryptamine; 5-HT) is a neurotransmitter and hormone whose effects are mediated through interactions at seven different families of receptor proteins, comprised of 14 different subtypes, consisting of 13 G-protein coupled receptors and one ligand-gated ion channel [1]. Serotonin is primarily known for its function as a neurotransmitter within the CNS, and is involved in many processes including cognition and memory [2]. Individual serotonin receptors are known to be expressed in many immune-related tissues [9]. We discovered that (R)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane [(R)-DOI], a highly selective agonist at serotonin 5-HT2 receptors, super-potently inhibits tumor necrosis factor alpha (TNF-a) induced inflammation in primary rat aortic smooth muscle (RASM) cells [10]. The anti-inflammatory effects include inhibition of TNF-a-induced expression of adhesion molecules (Icam-1, Vcam-1), cytokines (Il-6), nitric oxide synthase activity, and activation and nuclear translocation of NFkB in RASM cells with an IC50 of ,15 picomolar [10]. We determined that the anti-inflammatory effects of (R)-DOI are exclusively mediated through activation of serotonin 5-HT2A receptors [10]. We demonstrate that 5-HT2A receptor activation is mediating the anti-inflammatory response
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