The regulation of 5-HT- and 5-HT-expressing EC cells is intimately associated with the inflammatory processes that drive many GI disorders. Recent studies on EC cells and 5-HT have generated a number of concepts that provide insight into how the immune and endocrine systems of the gut interface. It is evident from these studies that mediators from immune cells such as cytokines have an important role in EC cell biology and production of 5-HT in the gut. In addition, 5-HT has a key role in the pathogenesis of experimental colitis and in generation of pro-inflammatory mediators from immune cells. If this is not complex enough, this entire relationship is occurring in the presence of varying diets and mediators secreted by the microbiota, which may directly or indirectly influence the EC cell function.
Recently, Margolis et al.75
has shown that inhibition of 5-HT synthesis using a specific inhibitor of the TpH1 enzyme reduces the severity of trinitrobenzene sulfonic acid-induced colitis in mice. This finding furthers supports our observation that 5-HT is a critical molecule in pathogenesis of colitis and suggest that targeted inhibition of 5-HT synthesis may ultimately help in the development of improved therapeutic strategies in GI inflammatory disorders.
5-HT exerts a wide range of effects in the gut, largely due to the presence of multiple receptor subtypes that are present on smooth muscle, enteric neurons, enterocytes, and immune cells. Agonist or antagonist for various 5-HT receptor is used in a variety of GI disorders, which include IBS, functional dyspepsia, and chronic constipation (). The 5-HT7
receptor, coupled to Gs proteins and stimulating cAMP production, is the most recently identified member of the family of 5-HT receptors. Our lab has evaluated the 5-HT7
receptor antagonist (SB-269970) and found that disruption of 5-HT7
receptor signaling significantly reduces the severity of both dextran sodium sulfate and dinitrobenzenesulfonic acid-induced colitis in mice.76
Pharmaco-modulation of 5-HT signaling using specific agonists and antagonists represents one of the best strategies for alleviating many of the symptoms associated with GI disease; however, the effect on the immune system should also be considered.