Received for publication July 14, 2008.
Revised August 14, 2008.
Accepted for publication August 14, 2008.

Serotonin 5-HT_2A receptor activation suppresses TNF--induced inflammation with extraordinary potency

Abstract

The G protein coupled serotonin 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. There is, however, 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 TNF--mediated inflammation. 5-HT_2A receptor stimulation with the agonist (R)-DOI rapidly inhibits a variety of TNF--mediated proinflammatory markers, including ICAM-1, VCAM-1, and IL-6 gene expression, NOS activity, and nuclear translocation of NF-B, with IC₅₀ values of only 10-20 pM. Significantly, proinflammatory markers also can 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. Importantly, 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.

Key words: NF-kB, TNF-alpha, aortic smooth muscle, atherosclerosis, inflammation, serotonin 5-HT2A receptor