Gastroenterology

Gastroenterology

Volume 132, Issue 3, March 2007, Pages 994-1008
Gastroenterology

Basic–alimentary tract
Inhibition of TGF-β Signaling by IL-15: A New Role for IL-15 in the Loss of Immune Homeostasis in Celiac Disease

https://doi.org/10.1053/j.gastro.2006.12.025Get rights and content

Background & Aims: Interleukin (IL)-15 delivers signals that drive chronic inflammation in several diseases, including celiac disease. Smad3–transforming growth factor-beta (TGF-β) 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-β in celiac disease. Methods: The impact of IL-15 on TGF-β 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-β 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-β–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-β–Smad-dependent transcription in biopsies of active celiac disease. c-jun antisense decreased interferon gamma transcription. Conclusions: Impairment of TGF-β-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.

Section snippets

CD Patients and Controls

Peripheral lymphocytes were from healthy volunteers. Histologically normal small intestinal samples were from 16 adults (age, 33–80 years; mean, 55 years) undergoing intestinal surgery for morbid obesity or pancreatic cancer. Duodenal biopsies were from 25 active CD adults (age, 18–70 years; mean age, 39 years) with partial to subtotal villous atrophy and positive serology for antiendomysium antibodies. This study was approved by the local ethics committee.

Lymphocyte Isolation and Cell Culture

Peripheral blood mononuclear cells

IL-15 Inhibits Smad3-Dependent TGF-β Signaling in Human T Lymphocytes

TGF-β1 plays a role in the negative regulation of the immune response in part by inhibiting normal T-cell proliferation after stimulation. Notably, TGF-β1, via activation of the Smad pathway, efficiently inhibits the proliferative response of T cells to IL-2,26 a cytokine that shares its receptor β and γ chains with IL-15.1 In agreement with previous reports,25, 27 TGF-β1 inhibited IL-2 induced proliferation of PBMC (Figure 1A). The inhibitory effect of TGF-β1, absent during the early phase of

Discussion

Our data, showing that IL-15 impedes Smad-dependent signaling of TGF-β, provide a new rationale for the potent proinflammatory effect of this cytokine that may be central to the pathogenesis of CD.

The inhibitory effect of IL-15 on TGF-β1 signaling in T lymphocytes was demonstrated by the negative impact of this cytokine on the formation of Smad–DNA complexes and on Smad3-dependent transcription. Consistent with these results and a previous report,27 TGF-β was unable to inhibit IL-15-induced

References (61)

  • F. Verrecchia et al.

    A central role for the JNK pathway in mediating the antagonistic activity of pro-inflammatory cytokines against transforming growth factor-beta-driven SMAD3/4-specific gene expression

    J Biol Chem

    (2003)
  • A.E. Hunt et al.

    Role of interleukin (IL)-2 receptor beta-chain subdomains and Shc in p38 mitogen-activated protein (MAP) kinase and p54 MAP kinase (stress-activated protein Kinase/c-Jun N-terminal kinase) activationIL-2-driven proliferation is independent of p38 and p54 MAP kinase activation

    J Biol Chem

    (1999)
  • F. Verrecchia et al.

    Tumor necrosis factor-alpha inhibits transforming growth factor-beta/Smad signaling in human dermal fibroblasts via AP-1 activation

    J Biol Chem

    (2000)
  • D. Korholz et al.

    The role of interleukin-10 (IL-10) in IL-15-mediated T-cell responses

    Blood

    (1997)
  • K. Ogawa et al.

    Transcriptional regulation of tristetraprolin by transforming growth factor-beta in human T cells

    J Biol Chem

    (2003)
  • E. Gronroos et al.

    Control of Smad7 stability by competition between acetylation and ubiquitination

    Mol Cell

    (2002)
  • D.D. Yang et al.

    Differentiation of CD4+ T cells to Th1 cells requires MAP kinase JNK2

    Immunity

    (1998)
  • E. Jacinto et al.

    Cooperation between Syk and Rac1 leads to synergistic JNK activation in T lymphocytes

    Immunity

    (1998)
  • S. Dubois et al.

    IL-15Ralpha recycles and presents IL-15 in trans to neighboring cells

    Immunity

    (2002)
  • I.B. McInnes et al.

    Interleukin-15: a new cytokine target for the treatment of inflammatory diseases

    Curr Opin Pharmacol

    (2004)
  • G.A. Taylor et al.

    A pathogenetic role for TNF alpha in the syndrome of cachexia, arthritis, and autoimmunity resulting from tristetraprolin (TTP) deficiency

    Immunity

    (1996)
  • M.O. Li et al.

    Transforming growth factor-beta controls development, homeostasis, and tolerance of T cells by regulatory T cell-dependent and -independent mechanisms

    Immunity

    (2006)
  • J.C. Marie et al.

    Cellular mechanisms of fatal early-onset autoimmunity in mice with the T cell-specific targeting of transforming growth factor-beta receptor

    Immunity

    (2006)
  • C. Cellier et al.

    Refractory sprue, coeliac disease, and enteropathy-associated T-cell lymphoma

    Lancet

    (2000)
  • T. Fehniger et al.

    Fatal leukemia in interleukin15 transgenic mice follows early expansion in natural killer and memory phenotype CD8+ T cells

    J Exp Med

    (2001)
  • N. Ohta et al.

    IL-15-dependent activation-induced cell death-resistant Th1 type CD8alphabeta(+)NK1.1(+) T cells for the development of small intestinal inflammation

    J Immunol

    (2002)
  • R.N. Bamford et al.

    The 5′ untranslated region, signal peptide, and the coding sequence of the carboxyl terminus of IL-15 participate in its multifaceted translational control

    J Immunol

    (1998)
  • B. Baslund et al.

    Targeting interleukin-15 in patients with rheumatoid arthritis: a proof-of-concept study

    Arthritis Rheum

    (2005)
  • L.S. Villadsen et al.

    Resolution of psoriasis upon blockade of IL-15 biological activity in a xenograft mouse model

    J Clin Invest

    (2003)
  • C.Y. Kim et al.

    Structural basis for HLA-DQ2-mediated presentation of gluten epitopes in celiac disease

    Proc Natl Acad Sci U S A

    (2004)

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    This work was sponsored by INSERM, by ARC Grant 4616, Canceropole Ile de France, and by La Fondation Princesse Grace de Monaco.

    The authors are grateful to members of the GERMC and particularly to Pr. M. Lehman (Hôpital Saint Louis), Dr. T. Matysiak-Budnik, Dr. D. Lamarque (Hôpital Hôtel Dieu), Pr. Chaussade (Hôpital Cochin), and Pr. Cugnenc (Hôpital Georges Pompidou) for providing material and information from their patients. The authors thank Dr. D. Buzoni-Gatel for helpful discussions and Mr. G. Pivert for technical support with histology.

    1

    M. Ben Ahmed was supported by INSERM, IRMAD, and AFDIAG (Association Française des Intolérants au Gluten).

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    Copyright © 2007 AGA Institute. Published by Elsevier Inc. All rights reserved.