A Functional Role of Flip in Conferring Resistance of Crohn’s Disease Lamina Propria Lymphocytes to FAS-Mediated Apoptosis

Ivan Monteleone,Giovanni Monteleone,Daniele Fina,Roberta Caruso,Carmelina Petruzziello,Emma Calabrese,Livia Biancone,Francesco Pallone

doi:10.1053/j.gastro.2005.10.021

Ivan Monteleone, Giovanni Monteleone + Show 6 more

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https://doi.org/10.1053/j.gastro.2005.10.021

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Journal: Gastroenterology	Publication Date: Feb 1, 2006
Citations: 29	License type: cc-by

Affiliation: University of Rome Tor Vergata

Abstract

There is evidence that, in Crohn's disease (CD), lamina propria T lymphocytes (LPLs) are resistant to FAS-mediated apoptosis and that this defect contributes to the mucosal T-cell accumulation. In this study we examined the functional role of Flip, a Flice inhibitor protein, in the resistance of CD LPL to FAS-mediated apoptosis. Biopsy specimens and LPLs were taken from CD and ulcerative colitis (UC) patients and normal controls and analyzed for Flip by Western blotting. We also examined whether inhibition of Flip by antisense oligonucleotide restored the susceptibility of CD LPLs to FAS-induced apoptosis. LPL apoptosis was assessed by flow cytometry. After FAS stimulation, the rate of apoptosis of CD3+ LPLs was higher in normal controls and patients with UC than in patients with CD. Enhanced expression of both long and short Flip isoforms was seen in biopsy specimens and purified CD3+ and CD45RO+ LPLs of CD patients in comparison with UC patients and normal controls. No increase in Flip was documented in untreated celiac disease mucosa, thus suggesting the possibility that induction of Flip in the gut does not simply rely on the ongoing inflammation. Finally, we showed that inhibition of Flip by antisense oligonucleotide reverted the resistance of CD LPLs to FAS-induced apoptosis. Data suggest a role for Flip in the resistance of CD LPLs to FAS-mediated apoptosis.

Highlights

Small bowel manipulation leads to a profound ileus and and an increase in spinal Fos expression suggesting prolonged activation of spinal afferent pathways
We investigated the activity of central nervous system (CNS) administered Orphanin FQ/Nociceptin (OFQ/N) on OFQ/N ligand knockout mice and in ORL-1 (OFQ receptor) knockout mice
We examined the latency for expulsion of a 3ram glass bead from the distal colon following intracerebrnventricular injection of OFQ/N or vehicle

Summary

Introduction

Small bowel manipulation leads to a profound ileus and and an increase in spinal Fos expression suggesting prolonged activation of spinal afferent pathways. Conclusions: The present study suggests that the Rbol ROCK pathway is involved in the control of actin network and in regulation of CTGF expression associated with radiation-induced fibrogenic differentiation. To evaluate the protective effects of folate we studied folate deplete (0 mg/kg), replete (2 mg/kg), and supplemented (8 mg/kg) diets in 8wk male CF-1 mice in an AOM model of colon cancer with respect to crypt proliferation, ACF and tumor formation Methods: 232 mice (160 treated + 72 controls) divided between each of the 3 dietary group received proscribed diets for 4 wks followed by injection with lOmg/ kg AOM sc or saline in 6 divided doses. Conclu sions Folate supplementation had no demonstrated chemopreventive or antiproliferative effects in this colon carcinogen model, r

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