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

  title={Serotonin 5-Hydroxytryptamine2A Receptor Activation Suppresses Tumor Necrosis Factor-$\alpha$-Induced Inflammation with Extraordinary Potency},
  author={Bangning Yu and Jaime Becnel and Mourad Zerfaoui and R. K. Rohatgi and A Hamid Boulares and Charles D. Nichols},
  journal={Journal of Pharmacology and Experimental Therapeutics},
  pages={316 - 323}
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-HT2A receptors in primary aortic smooth muscle cells provides a previously unknown and extremely potent… 

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Serotonin 5-HT2A Receptor Activation Blocks TNF-α Mediated Inflammation In Vivo

It is demonstrated 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, and indicates 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.

Recent advances in 5-hydroxytryptamine (5-HT) receptor research: how many pathophysiological roles does 5-HT play via its multiple receptor subtypes? Foreword.

  • M. Hirafuji
  • Biology
    Biological & pharmaceutical bulletin
  • 2013
It is believed that increasing evidence on the role of 5-HT receptors will contribute to the expansion of the clinical application of existing therapeutic drugs such as sarpogrelate, and to the development of new 5- HT receptor-related drugs for treating cardiovascular diseases.

5-hydroxytryptamine and its receptors in systemic vascular walls.

It is believed that increasing evidence on the role of 5-HT receptors will contribute to the expansion of the clinical application of existing therapeutic drugs such as sarpogrelate, and to the development of new 5- HT receptor-related drugs for treating cardiovascular diseases.

The Effects of Serotonin in Immune Cells

Serotonin can also suppress the release of tumor necrosis factor-α and interleukin-1β by activating serotonin receptors, and neutrophil recruitment and T-cell activation can both be mediated by serotonin.

Serotonin 5-HT2A receptor activity mediates adipocyte differentiation through control of adipogenic gene expression

Time course analysis indicates that 5‐HT2A receptor activity is necessary very early in the induction phase to facilitate differentiation, and data demonstrating that blockade of 5‐ HT2A activity inhibits adipocyte differentiation indicate that 5-HT2a receptors play an important role in adipocytes differentiation.

Serotonin stimulates platelet receptor shedding by tumor necrosis factor‐alpha‐converting enzyme (ADAM17)

Stimulation of 5‐HT2AR on platelets induces TACE‐mediated shedding of GPIbα, the key adhesion molecule under high shear conditions, demonstrating a new pathway through which 5‐ HT could modulate cardiovascular disease.

Activation of 5-HT2 Receptors Reduces Inflammation in Vascular Tissue and Cholesterol Levels in High-Fat Diet-Fed Apolipoprotein E Knockout Mice

The putative therapeutic effects of (R)-DOI in the ApoE−/− high fat model of cardiovascular disease is examined and activation of 5-HT2A receptors at sub-behavioral levels may represent a new strategy to treat inflammation-based cardiovascular disease.

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

Serotonin 5-HT₂ receptor activation prevents allergic asthma in a mouse model.

In the ovalbumin mouse model of allergic inflammation, it is demonstrated that inhalation of (R)-DOI prevents the development of many key features of allergic asthma, including AHR, mucus hyperproduction, airways inflammation, and pulmonary eosinophil recruitment.



Serotonin Increases Interleukin-6 Synthesis in Human Vascular Smooth Muscle Cells

5-HT acts on 5-HT2A receptors and increases IL-6 synthesis in human VSMCs at least partially through a PKC-dependent pathway and is suggested to contribute to inflammatory activation of the vessels during atherogenesis.

Functions of 5-HT2A receptor and its antagonists in the cardiovascular system.

Differential effect of serotonin on cytokine production in lipopolysaccharide-stimulated human peripheral blood mononuclear cells: involvement of 5-hydroxytryptamine2A receptors.

The findings suggest that the inhibition of TNF-alpha production by 5- HT involves the participation of the 5-HT(2A) receptor subtypes in PBMC, and support a role of 5-ht in inflammation through its effect on cytokine production inPBMC.

Serotonin 5-Hydroxytryptamine2A Receptor-Coupled Phospholipase C and Phospholipase A2 Signaling Pathways Have Different Receptor Reserves

The data support the hypothesis of agonist-directed trafficking in NIH3T3–5HT2A cells because structurally distinct ligands were able to induce preferential activation of the PLC or PLA2 signaling pathway and conclude that structurally different ligands can differentially regulate 5-HT 2A receptor signal transduction.

Serotonin 5‐HT2A Receptor Activation Inhibits Cytokine‐stimulated Inducible Nitric Oxide Synthase in C6 Glioma Cells a

There is a link between the serotonergic system and NO‐mediated immune responses in the brain and the effectiveness of DOI was lost when added more than two hours after the addition of inducing agent, suggesting that DOI was regulating iNOS at the level of transcription rather than post‐translationally.

mRNA Expression of Serotonin Receptors in Cells of the Immune Tissues of the Rat

The results of this study may be useful as a starting point for future functional studies on immunomodulatory effects of 5-HT and may help to understand conflicting serotonergic effects on immune functions as found in the literature.