Gastroenterology
Volume 132, Issue 3 , Pages 1174-1176, March 2007

Mucosal Inflammation in Celiac Disease: Interleukin-15 Meets Transforming Growth Factor β-1

  • Martin F. Kagnoff

      Affiliations

    • Corresponding Author InformationAddress requests for reprints to: Martin F. Kagnoff, MD, Professor of Medicine and Pediatrics, Wm. K. Warren Medical Research Center for Celiac Disease, Room 412 MTF Building, University of California at San Diego, 9500 Gilman Drive, La Jolla, California 92093-0623. fax: (858) 534-5691.

Wm. K. Warren Medical Research Center for Celiac Disease, University of California at San Diego, La Jolla, California

Article Outline

 

See “Inhibition of TGF-β signaling by IL-15: A new role for IL-15 in the loss of immune homeostasis in celiac disease” by BenAhmed M, Meresse B, Arnulf B, Barbe U, Mention J–J, Verkarre V, Allez M, Cellier C, Hermine O, and Cerf–Bensussan N, on page 994.

Susceptibility to celiac disease (CD), its activation, and perpetuation involves interactions between environmental and genetic factors, and the interplay of host innate and adaptive immune responses.1 CD is activated by the dietary ingestion of wheat gluten (a mixture of gliadins and glutenins) or similar glutamine- and proline-rich proteins in barley (hordeins) and rye (secalins), hereafter referred to as gluten. As recently reviewed, CD occurs in approximately 1% of the US population and can present with a broad spectrum of intestinal and extraintestinal symptoms.2, 3

Several significant recent advances in understanding the pathogenesis of CD have focused on the importance and mechanism by which “gluten” peptides activate pathogenic CD4+ T-cell responses in the intestinal mucosa.1 Gluten, which is rich in the amino acid proline, is incompletely digested in the upper small intestine because the human small intestinal mucosa is relatively deficient in prolyl endopeptidases. This results in the generation of relatively large and potentially disease activating proline and glutamine-rich “gluten” peptides in the small intestine.4, 5 In addition, susceptibility to CD requires that the host carries human leukocyte antigen (HLA) class II DQ alleles (either in cis or trans) that can code for specific HLA class II DQ2 or DQ8 molecules. Those HLA class II DQ2 or DQ8 molecules have the unique ability to bind a range of glutamine and proline rich “gluten” peptides and contribute to CD pathogenesis by activating populations of “gluten”-specific CD4+ T cells in the small intestinal mucosa. Binding of gluten peptides to those DQ2 and DQ8 molecules is strongly favored when certain glutamines are deamidated to yield negatively charged glutamic acid residues by the action of tissue transglutaminase.6, 7, 8 “Gluten”-specific CD4+ T cells produce mediators (eg, interferon-γ) that activate further pathways that cause small intestinal mucosal damage. Although inheriting genes that encode the HLA class II molecules DQ2 or DQ8 is a requisite to develop CD, this alone is not sufficient. Thus, the vast majority of individuals who carry DQ2 or DQ8 and ingest “gluten” do not develop CD. This led to the search for additional genetic, environmental, and host factors that predispose to CD.

The role of innate immunity in the pathogenesis of CD and the nature of the putative link between innate immunity and the “gluten”-specific DQ2 or DQ8 restricted adaptive CD4+ T-cell response has emerged recently as a major research frontier.9, 10, 11 Key components of the mucosal innate immune system that have taken center stage as potentially important in the pathogenesis of CD include intestinal epithelial cells (IECs), intraepithelial lymphocytes (IELs), dendritic cells (DCs), and the cytokines, receptors and ligands that mediate cross-talk among those cell populations and with cells of the adaptive immune system.12, 13, 14, 15, 16, 17 The cytokine interleukin (IL)-15 has emerged as being particularly important in this regard.

IL-15 mediates many of its pleiotropic biological activities by functioning as a cell surface membrane associated cytokine that signals neighboring target cells through their cell surface IL-15 receptor.18 IL-15 is important in the development, differentiation, and function of subsets of intestinal IEL T-cell populations (eg, CD8αα/TCRαβ IEL), natural killer (NK), and NK–T cells19, 20, 21, 22 and can alter signaling properties and increase cytotoxic activity of IEL populations.14, 15, 23, 24, 25 In addition, IL-15 induces the expression of surface ligands on IECs (eg, MHC class I–related chain A [MICA]) that serve as targets for cytotoxic IEL.14, 16, 25 IL-15 can activate proinflammatory responses as well as mediate anti-apoptotic activities, the latter of which can be epithelial cell protective.26, 27

IL-15 production by IECs, DCs, and macrophages is markedly increased in the mucosa of active CD patients.9, 12, 14, 24, 25, 28 Although the specific mechanism(s) responsible for up-regulated expression of IL-15 in CD have not been fully defined, several reports indicate that certain “gluten” peptides derived from α-gliadin (eg, peptides 31–43 and 31–49), which are distinct from those that bind DQ2 or DQ8 and activate “gluten” peptide–specific CD4+ T cells, can up-regulate IL-15 production by IECs.9, 25 IL-15 acting on IELs and IECs results in up-regulated IEL cytotoxicity for IECs that is mediated, in part, by NKG2D receptor recognition of IL-15–induced stress molecules (ie, MICA) on IECs.14, 25

The article by Ahmed et al29 in the current issue of Gastroenterology is novel in that it addresses a mechanism by which increased IL-15 production might contribute to the inflammatory response in CD by interfering with important anti-inflammatory pathways that are normally activated in the small intestinal mucosa by the cytokine transforming growth factor (TGF)-β1. TGF-β1 has an important role in the intestinal mucosa in down-regulating mucosal inflammation as well as in the development of oral tolerance and mucosal IgA responses.30, 31, 32 Active TGF-β1 signaling through cell surface TGF-β receptors activates a complex that contains the proteins Smad 2, 3, and 4. This complex translocates to the nucleus where it increases the transcription of TGFβ-1 target genes. Because TGF-β1 target genes activate important anti-inflammatory pathways, disruption of TGF-β1 signaling at a variety of points ranging from the initial activation of the cell surface TGF-β1 receptor to the downstream activity of TGF-β1 on its target genes, can result in increased intestinal inflammation.

TGF-β1 is known to inhibit T-cell proliferation in response to agonists like IL-2. However, Ahmed et al29 found that TGF-β1 did not block IL-15–induced proliferation of peripheral blood mononuclear cells (PBMC), IELs, or lamina propria lymphocytes (LPL). Rather than simply assume that TGF-β1 lacks activity on IL-15–induced proliferation in those cells, the authors investigated an alternative possibility, namely, that IL-15 inhibits TGF-β1 signaling in those cells. Based on a series of studies using PBMC, IEL, and LPL, and duodenal biopsy specimens from controls and patients with CD, Ahmed et al29 conclude that IL-15 inhibits TGF-β1 signaling in T cells. Investigations to determine the specific mechanism(s) responsible for inhibiting TGF-β1 signaling indicated that inhibition occurs late in the signaling cascade. IL-15–induced inhibition of TGF-β1 signaling seemed to take place downstream from the nuclear translocation of the Smad complex, and to be due to increased activation of c-jun–N-terminal kinase (JNK) and the increased generation of phospho–c-jun, rather than through altered TGF-β receptor expression or signaling, Smad 2 or 3 phosphorylation, or up-regulation of Smad 7, the latter being known to block Smad 2 and 3 phosphorylation. Consistent with their finding, JNK activation had previously been reported to antagonize TGF-β1–induced Smad signaling in other systems.33 Additional studies suggested that early steps in TGF-β1 signaling were intact in CD patients and experiments using IEL and LPL isolated from human duodenal biopsies of CD patients and controls indicated that phospho–c-jun expression was increased only in patients with active CD. It is possible that the latter finding simply reflects, in part, increased JNK activation and increased phospho–c-jun secondary to increased T-cell activation34 in IEL and LPL from CD patients, independent of IL-15. However, studies using CD biopsies cultured with anti–IL-15 antibody in organ culture suggested this may not be the case. Nonetheless, the kinetics of the responses observed in the current study raise the question of whether IL-15 in fact acts directly on TGF-β1 signaling activity or if inhibition of TGF-β1 activity in response to IL-15 is secondary to the activation of another mediator downstream of IL-15.

The overall significance of this report lies in the demonstration that IL-15, which is markedly up-regulated in the mucosa of active CD patients, can impede TGF-β1 signaling in mucosal T cells, irrespective of the specific point at which signaling is impeded. This provides an additional, and possibly very important, pathway by which IL-15 could mediate proinflammatory effects that are functionally relevant in the pathogenesis of CD. Therefore, it is essential for future studies to determine if IL-15, in fact, prevents TGF-β1 from inhibiting essential T-cell effector activities such as cytokine secretion, T-cell proliferation, or cytotoxicity in vivo, all of which likely are significant in CD pathogenesis. For example, does IL-15 abrogate TGF-β1–mediated inhibition of IEL-mediated epithelial damage14, 16, 25 or gluten-specific CD4 T-cell responses?

Emerging concepts of CD pathogenesis indicate that both innate and adaptive T-cell immune responses are necessary for the phenotypic expression and pathologic changes characteristic of CD and either type of response alone may not be sufficient to induce “full-blown” disease. This may be one factor that could help to explain why most individuals with DQ2 or DQ8 do not develop CD. Finally, IL-15, by virtue of its anti-apoptotic effects and proinflammatory activities, has been postulated to have a key role in the development of refractory CD, and the rare complication of T-cell lymphomas in patients with CD.24 This study by Ahmed et al29 offers another pathway by which increased IL-15 may contribute to the pathogenesis of CD and further supports the notion that IL-15 may be a useful therapeutic target in CD and particularly in refractory CD, where the risk of developing T-cell lymphoma is much greater. Such therapies are now becoming possible with the advent of monoclonal anti–IL-15 antibodies35 and pharmacologic agents that can selectively block key IL-15 signal transduction pathways.

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 M.F.K. is supported by a grant from the Wm. K. Warren Foundation and National Institutes of Health grants DK35108 and DK58960.

PII: S0016-5085(07)00334-4

doi:10.1053/j.gastro.2007.01.062

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Gastroenterology
Volume 132, Issue 3 , Pages 1174-1176, March 2007

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