Potential role of the IL-33/ST2 axis in celiac disease

Abstract

The IL-33/ST2 axis has been implicated in the pathogenesis of several tissue-specific autoimmune diseases. Celiac disease (CD) is the only autoimmune disease in which both the major genetic factors (HLA-DQ2/DQ8) and etiologic ones (dietary gluten) for susceptibility are known. We have measured serum levels and determined intestinal tissue expression of IL-33 and its receptor soluble ST2 in patients with CD to investigate their association with disease activity. Serum and tissue levels of both IL-33 and sST2 were significantly higher in patients with CD compared with those in control patients without CD. We show that toxic peptides extracted from barley and wheat gliadin significantly stimulate the production of IL-33 and ST2 in cultured peripheral blood mononuclear cell from celiac patients, strongly implicating the IL-33/ST2 axis in the pathogenesis of CD. The higher levels of IL-33 and its receptor ST2 in tissue and serum reflect an active inflammatory state and may represent a potential biomarker for disease activity. A better understanding of IL-33/ST2 release, mode of action, and regulation will be crucial to develop therapeutics that target the IL-33/ST2 pathway to treat CD.Cellular & Molecular Immunology advance online publication, 7 September 2015; doi:10.1038/cmi.2015.85.

Figure 1

Immunohistochemistry analysis: (a) Immunostaining for IL-33 in celiac disease patients (n = 20), showing expression in epithelial and lamina propria cells. (b) Immunostaining for IL-33 in Crohn's disease patients (n = 7). (c) Immunostaining for ST2 in CD patients showing expression in Lieberkhün crypts. (d) Immunoreaction for ST2in Crohn's disease patients; (e) IL-33 expression in control patients (n = 8); (f) ST2 expression in control patients. Magnification: ×200.

Figure 2

IL-33 and sST2 expression in the serum of celiac disease, control health, and Crohn's disease patients. IL-33 and sST2 were highly expressed in the serum from celiac disease patients (n = 20) in comparison with control (n = 8) and Crohn's disease (n = 7). Significantly different at *p < 0.05 are shown.

Figure 3

IL-33 (a) and sST2 levels (b) in culture supernatants of PBMCs (n = 15) with different toxic peptides in comparison with control (rice). Significantly different at **p < 0.005 are shown.

Figure 4

(a) IFN-γ production by PBMCs with different peptides incubation. (b) Proliferative responses of PBMCs to different peptides. In A and B, the results are expressed as mean ± SD of duplicated cultures (n = 15 CD patients). Significantly differences with respect control at **p < 0.005 are shown. Gliadin was used as the positive control in PBMCs cultures and rice as control (negative).