Epithelium derived interleukin 15 regulates intraepithelial lymphocyte Th1 cytokine production, cytotoxicity, and survival in coeliac disease
- A Di Sabatino1,
- R Ciccocioppo2,
- F Cupelli2,
- B Cinque2,
- D Millimaggi2,
- M M Clarkson2,
- M Paulli3,
- M G Cifone2,
- G R Corazza1
- 1First Department of Medicine, IRCCS Policlinico S Matteo, University of Pavia, Pavia, Italy
- 2Department of Experimental Medicine, University of L’Aquila, L’Aquila, Italy
- 3Department of Pathology, IRCCS Policlinico S Matteo, University of Pavia, Pavia
- Correspondence to:
Professor G R Corazza
Clinica Medica I, IRCCS Policlinico San Matteo, Piazzale Golgi 5, 27100 Pavia, Italy;
- Accepted 8 August 2005
- Revised 4 August 2005
- Published Online First 16 August 2005
Background and aims: Epithelium derived interleukin (IL)-15 signalling via IL-15Rα is critical for the development, activation, and survival of intraepithelial lymphocytes (IEL). We aimed to better understand the IL-15 driven effects on IEL underlying mucosal damage and lymphomagenesis in coeliac disease (CD).
Methods: Enterocytes, IEL, and lamina propria mononuclear cells (LPMC) were isolated from 46 patients with uncomplicated CD (25 untreated and 21 treated) and 22 controls. IL-15 and IL-15Rα expression were determined by immunoblotting. Secretion of IL-15, interferon γ (IFN-γ), tumour necrosis factor α (TNF-α), and granzyme B into cell culture supernatants was assessed by ELISA. The ability of IL-15 to regulate IEL proliferation, perforin/granzyme dependent cytotoxicity, and apoptosis was tested by adding different combinations of IL-15, IL-15 blocking antibody, or chloroquine to IEL cultured alone or with Caco-2 cells as target. IL-15 mucosal levels were also determined by ELISA in five patients with complicated CD (two ulcerative jejunoileites, one refractory sprue, and two enteropathy associated T cell lymphomas) tested for T cell receptor γ chain clonality.
Results: IL-15 was overexpressed in untreated CD enterocytes and LPMC, and in the mucosa of complicated CD patients and uncomplicated untreated CD patients, where its levels correlated with the degree of mucosal damage. Enterocytes from untreated, but not treated, CD patients and controls secreted IL-15. Untreated CD IEL, characterised by higher IL-15Rα expression, showed increased proliferation, production of IFN-γ and TNF-α, and perforin/granzyme dependent cytotoxicity, and a decreased propensity to apoptosis in response to IL-15.
Conclusions: Our findings suggest that IL-15 plays a crucial role in the generation of epithelial damage in active CD. Its promotion of IEL survival in CD may predispose to the emergence of T cell clonal proliferations. Blocking IL-15, by suppressing uncontrolled IEL activation and survival, has the potential to provide new therapeutic tools to prevent tissue damage and lymphomagenesis in CD.
- CD, coeliac disease
- EDTA, ethylenediamine-tetraacetic acid
- FITC, fluorescein isothiocyanate
- IFN, interferon
- IL, interleukin
- IEL, intraepithelial lymphocyte
- LPMC, lamina propria mononuclear cell
- LPS, lipopolysaccharide
- PI, propidium iodide
- TCR-γ, T cell receptor γ chain
- TNF, tumour necrosis factor
- coeliac disease
- interleukin 15
- intraepithelial lymphocyte
- T cell lymphoma
Published online first 16 August 2005
Conflict of interest: None declared.