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THE IMMUNE-ENDOCRINE AXIS: ROLE OF IL-13 IN EC CELL BIOLOGY AND 5-HT PRODUCTION
M Manocha1, M Shajib1, H Wang1, M Rahman1, M Bogunovic2, L Mayer2, W Khan11McMaster University, Hamilton, ON; 2The Mount Sinai School of Medicine, New York, New York, USA
Aims: Enterochromaffin (EC) cells in the epithelium of the gastrointestinal (GI) tract are the largest producers of serotonin (5-hydroxytryptamine; 5-HT) in the body. 5-HT is considered an important regulator of intestinal homeostasis and is implicated in the pathophysiology of many GI disorders which include functional and inflammatory bowel diseases. Nevertheless, the mechanism by which 5-HT is produced from EC cells remains to be determined. Previously we have shown up-regulation of 5-HT expressing EC cell numbers and 5-HT production in a mouse model of nematode infection in association with increased Th2 immune response. We also reported presence of interleukin (IL) - 13 receptor alpha1 on EC cells revealing a potential link between IL-13 and EC cell biology.
Hypothesis: IL-13 plays an important role in generation of EC cell hyperplasia and in production of 5-HT.
Methods: IL-13 KO and wild-type mice were infected with nematode, Trichuris muris and sacrificed on different days post-infection (pi) to study 5-HT expressing EC cells, and 5-HT amount in colon. Naïve IL-13 KO mice were treated with recombinant IL-13 (2 µg/mouse/day; ip) or vehicle (PBS) for 5 days, upon which time the colon was excised and 5-HT content of colon and the numbers of 5-HT expressing EC cells were examined. To further confirm the role of IL-13 in 5-HT production BON cells (human carcinoid tumour of EC cell origin) were stimulated in vitro with recombinant IL-13. 5-HT amount was assessed in the culture media and the number of BON cells was counted using both a haemocytometer and alamarBlue cell proliferation assay.
Results: 5-HT expressing EC cells numbers and 5-HT amount in colon were significantly lower in IL-13 KO mice as compared to the wild type mice after T. muris infection. Reconstitution of IL-13 in IL-13 KO mice resulted in a significant increase of 5-HT content in the colon, which was accompanied by a significantly increased number of 5-HT expressing EC cells. Treatment of BON cells with human recombinant IL-13 resulted in a small but significant increase of 5-HT content in the cell culture media and this was associated with a 26% to 45% increase in the number of BON cells in culture.
Conclusions: Our results demonstrate an important role for IL-13 in EC cell biology. IL-13 facilities the increase of 5-HT expressing EC cells numbers in both an in vivo mouse model and in culture human model of EC cells, These observations provide new information on the immuno-endocrine axis in gut which may ultimately lead to effective strategies to modulate 5-HT response in various GI disorders.