Abstract
Background and ObjectivesDamage to intestinal mucosa in celiac disease (CD) is mediated both by inflammation due to adaptive and innate immune responses, with IL-15 as a major mediator of the innate immune response, and by proliferation of crypt enterocytes as an early alteration of CD mucosa causing crypts hyperplasia. We have previously shown that gliadin peptide P31-43 induces proliferation of cell lines and celiac enterocytes by delaying degradation of the active epidermal growth factor receptor (EGFR) due to delayed maturation of endocytic vesicles. IL-15 is increased in the intestine of patients affected by CD and has pleiotropic activity that ultimately results in immunoregulatory cross-talk between cells belonging to the innate and adaptive branches of the immune response. Aims of this study were to investigate the role of P31-43 in the induction of cellular proliferation and innate immune activation.Methods/Principal FindingsCell proliferation was evaluated by bromodeoxyuridine (BrdU) incorporation both in CaCo-2 cells and in biopsies from active CD cases and controls. We used real-time PCR to evaluate IL-15 mRNA levels and FACS as well as ELISA and Western Blot (WB) analysis to measure protein levels and distribution in CaCo-2 cells.Gliadin and P31-43 induce a proliferation of both CaCo-2 cells and CD crypt enterocytes that is dependent on both EGFR and IL-15 activity. In CaCo-2 cells, P31-43 increased IL-15 levels on the cell surface by altering intracellular trafficking. The increased IL-15 protein was bound to IL15 receptor (IL-15R) alpha, did not require new protein synthesis and functioned as a growth factor.ConclusionIn this study, we have shown that P31-43 induces both increase of the trans-presented IL-15/IL5R alpha complex on cell surfaces by altering the trafficking of the vesicular compartments as well as proliferation of crypt enterocytes with consequent remodelling of CD mucosa due to a cooperation of IL-15 and EGFR.
Highlights
Celiac disease (CD) is characterised by derangement of both the adaptive and the innate immune responses to gliadin, that is a storage protein of wheat
In this study, we have shown that P31-43 induces both increase of the trans-presented IL-15/IL5R alpha complex on cell surfaces by altering the trafficking of the vesicular compartments as well as proliferation of crypt enterocytes with consequent remodelling of celiac disease (CD) mucosa due to a cooperation of IL-15 and epidermal growth factor receptor (EGFR)
We found that the so-called gliadin toxic peptide (P31-43) delays endocytic vesicle maturation and reduces epidermal growth factor receptor (EGFR) degradation and prolongs EGFR activation, which in turn results in increased cell proliferation and actin modifications in celiac crypt enterocytes and in various cells lines [9]
Summary
Celiac disease (CD) is characterised by derangement of both the adaptive and the innate immune responses to gliadin, that is a storage protein of wheat. P31-43 enters CaCo-2 cells and intestinal enterocytes, interacts with early endocytic vesicles [10,11], reduces their motility and delays their maturation to late endosomes [10] Taken together, this information points toward an effect of certain gliadin peptides, i.e., P31-43, on endocytic function and indicates epidermal growth factor (EGF) signalling as one of the major pathways in the celiac intestine. Damage to intestinal mucosa in celiac disease (CD) is mediated both by inflammation due to adaptive and innate immune responses, with IL-15 as a major mediator of the innate immune response, and by proliferation of crypt enterocytes as an early alteration of CD mucosa causing crypts hyperplasia. Aims of this study were to investigate the role of P31-43 in the induction of cellular proliferation and innate immune activation
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