Inhibition of TGF-beta signaling by IL-15: a new role for IL-15 in the loss of immune homeostasis in celiac disease.
OBJECTIVE
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.
Benahmed
Mélika
M
INSERM U793, Paris, France.
Meresse
Bertrand
B
Arnulf
Bertrand
B
Barbe
Ullah
U
Mention
Jean-Jacques
JJ
Verkarre
Virginie
V
Allez
Matthieu
M
Cellier
Christophe
C
Hermine
Olivier
O
Cerf-Bensussan
Nadine
N
D021581:Active Transport, Cell Nucleus; D000328:Adult; D000368:Aged; D002446:Celiac Disease / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D004789:Enzyme Activation; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics; D006706:Homeostasis / Q000276:immunology; D006801:Humans; D018928:Immunity, Mucosal; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D019409:Interleukin-15 / Q000096:biosynthesis* / Q000494:pharmacology; D007376:Interleukin-2 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008875:Middle Aged; D009924:Organ Culture Techniques; D010766:Phosphorylation; D012333:RNA, Messenger / Q000096:biosynthesis; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D051900:Smad3 Protein / Q000378:metabolism; D051906:Smad7 Protein / Q000096:biosynthesis / Q000235:genetics; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D013997:Time Factors; D014158:Transcription, Genetic; D053773:Transforming Growth Factor beta1 / Q000378:metabolism* / Q000494:pharmacology; D051816:Tristetraprolin / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation
D018398:Homeodomain Proteins; D019409:Interleukin-15; D007376:Interleukin-2; D012333:RNA, Messenger; D012097:Repressor Proteins; C497790:SMAD3 protein, human; C497806:SMAD7 protein, human; D051900:Smad3 Protein; D051906:Smad7 Protein; C097504:TGIF1 protein, human; D053773:Transforming Growth Factor beta1; D051816:Tristetraprolin; C497552:ZFP36 protein, human; D007371:Interferon-gamma; D048031:JNK Mitogen-Activated Protein Kinases