IFN-γ and TNF-α decrease serotonin transporter function and expression in Caco2 cells

Abstract

Foley KF, Pantano C, Ciolino A, Mawe GM. IFN-␥ and TNF-␣ decrease serotonin transporter function and expression in Caco2 cells. Am J Physiol Gastrointest Liver Physiol 292: G779 -G784, 2007. First published December 14, 2006; doi:10.1152/ajpgi.00470.2006.-Recent studies have shown that mucosal serotonin (5-HT) transporter (SERT) expression is decreased in animal models of colitis, as well as in the colonic mucosa of humans with ulcerative colitis and irritable bowel syndrome. Altered SERT function or expression may underlie the altered motility, secretion, and sensation seen in these inflammatory gut disorders. In an effort to elucidate possible mediators of SERT downregulation, we treated cultured colonic epithelial cells (Caco2) with conditioned medium from activated human lymphocytes. Application of the conditioned medium caused a decrease in fluoxetine-sensitive [3 H]5-HT uptake. Individual proinflammatory agents were then tested for their ability to affect uptake. Cells were treated for 48 or 72 h with PGE2 (10 M), IFN-␥ (500 ng/ml), TNF-␣ (50 ng/ml), IL-12 (50 ng/ml), or the nitric oxide-releasing agent S-nitrosoglutathione (GSNO; 100 M).[ 3 H]5-HT uptake was then measured. Neither PGE nor IL-12 had any effect on [ 3 H]5-HT uptake, and GSNO increased uptake. However, after 3-day incubation, both TNF-␣ and IFN-␥ elicited significant decreases in SERT function. Neither TNF-␣ nor IFN-␥ were cytotoxic when used for this period of time and at these concentrations. These two cytokines also induced decreases in SERT mRNA and protein levels. By altering SERT expression, TNF-␣ and IFN-␥ could contribute to the altered motility and expression seen in vivo in ulcerative colitis or irritable bowel syndrome.SERT; tumor necrosis factor; interferon; colitis; inflammatory bowel disease; inflammation SEROTONIN (5-hydroxytryptamine; 5-HT) is the main monoamine signaling molecule in the gut, where it acts as a paracrine neurotransmitter (9, 25). Specialized enteroendocrine cells, enterochromaffin cells, release 5-HT into the lamina propria of the intestines, where it activates receptors located on processes of intrinsic and extrinsic primary afferent neurons. This leads to activation of local motor and secretory reflexes and the transduction of sensory signals to the brain stem and spinal cord. A critical aspect of paracrine and neurotransmitter signaling is the termination of transmission by degradation or removal of the signaling molecule. In the case of 5-HT, this involves rapid clearance of 5-HT from the intercellular space by the 5-HT reuptake transporter (SERT), which is expressed by mucosal epithelial cells (7,21,36).SERT is a member of the highly conserved Na ϩ /Cl Ϫ -dependent transporter gene family containing 12 transmembrane domains (2). Transporters for 5-HT and other monoamines are of particular interest because they are sites of action for most clinically efficacious antidepressants, as well as for psychoactive drugs of abuse such as amphetamines, cocaine, and MDMA (ecstasy). Furthermore, abnormal expression o...

The Pro-inflammatory Cytokine TNF-α Regulates the Activity and Expression of the Serotonin Transporter (SERT) in Astrocytes

“…Studies conducted in the same cell line following treatment for up to 72 h with the pro-inflammatory cytokines TNF-a and IL-6 revealed that TNF-a but not IL-6 treatment resulted in an increase in the V max for 5-HT transport in these cells [25]. Others have found a downregulation of SERT by TNF-a in enterocyte-like Caco-2 cells [43], suggesting cell-type specific effects of TNF-a.…”

Regulation of serotonin transporter activity by adenosine in intestinal epithelial cells

“…Recent reports have confirmed the relevance of the SERT function for the control of intestinal activity [30,31]. SERT expression and activity are affected in intestinal inflammation [10,[14][15][16] and inflammatory mediators have been shown to inhibit SERT function and expression in epithelial cells [12,13].…”

“…As indicated above, it is well established that intestinal inflammation coincides with decreased SERT activity and inflammatory mediators inhibit SERT function and expression in epithelial cells [12,13]. Adenosine also plays a role in 3 intestinal inflammatory response although its role as a mediator that may evoke SERT alteration remains unclear.…”

“…Recent results have demonstrated that SERT expression is downregulated and SERT activity is impaired in intestinal epithelial cells treated with pro-inflammatory factors [12,13], in animal models and human forms of intestinal inflammation [10,[14][15][16].…”

Fundamentals of Neurogastroenterology: Basic Science

“…20 The contributing factors for decreased SERT in IBS have not been identified, but it may involve a genetic predisposition, given that certain polymorphisms of the SERT gene are associated with decreased SERT expression. It also is possible that altered SERT expression in IBS develops as a compensatory response to altered gut function; however, SERT expression is not altered in opiate-induced constipation.…”