Inhibition of TGF-beta signaling by IL-15: a new role for IL-15 in the loss of immune homeostasis in celiac disease.

Abstract:

BACKGROUND AND AIMS:Interleukin (IL)-15 delivers signals that drive chronic inflammation in several diseases, including celiac disease. Smad3-transforming growth factor-beta (TGF-beta) signaling is instrumental to counteract proinflammatory signals and maintain immune homeostasis. Our goal has been to investigate why the proinflammatory effects of IL-15 cannot be efficiently controlled by TGF-beta in celiac disease. METHODS:The impact of IL-15 on TGF-beta signaling in T cells and in the intestinal mucosa of celiac disease patients was analyzed by combining cell and organ cultures, immunohistochemistry, flow cytometry, real-time polymerase chain reaction, electromobility gel shift, and Western blot. RESULTS:IL-15 impaired Smad3-dependent TGF-beta signaling in human T lymphocytes downstream from Smad3 nuclear translocation. IL-15-mediated inhibition was associated with a long-lasting activation of c-jun-N-terminal kinase and reversed by c-jun antisense oligonucleotides, consistent with the demonstrated inhibitory effect of phospho-c-jun on the formation of Smad3-DNA complexes. In active celiac disease, intestinal lymphocytes showed impaired TGF-beta-Smad3-dependent transcriptional responses and up-regulation of phospho-c-jun. Anti-IL-15 antibody and c-jun antisense both downmodulated phospho-c-jun expression and restored TGF-beta-Smad-dependent transcription in biopsies of active celiac disease. c-jun antisense decreased interferon gamma transcription. CONCLUSIONS:Impairment of TGF-beta-mediated signaling by IL-15 might promote and sustain intestinal inflammation in celiac disease. More generally, our data provide a new rationale for the potent proinflammatory effects of IL-15, and further support the concept that IL-15 is a meaningful therapeutic target in inflammatory diseases associated with irreducible elevation of IL-15.

journal_name

Gastroenterology

journal_title

Gastroenterology

authors

Benahmed M,Meresse B,Arnulf B,Barbe U,Mention JJ,Verkarre V,Allez M,Cellier C,Hermine O,Cerf-Bensussan N

doi

10.1053/j.gastro.2006.12.025

subject

Has Abstract

pub_date

2007-03-01 00:00:00

pages

994-1008

issue

3

eissn

0016-5085

issn

1528-0012

pii

S0016-5085(06)02675-8

journal_volume

132

pub_type

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