Pathogenic role of IL-33-mediated eosinophil infiltration and function in experimental inflammatory bowel disease

De Salvo, Carlo (2013) Pathogenic role of IL-33-mediated eosinophil infiltration and function in experimental inflammatory bowel disease, [Dissertation thesis], Alma Mater Studiorum Università di Bologna. Dottorato di ricerca in Scienze chirurgiche: progetto n. 4 "Scienze medico-chirurgiche gastroenterologiche e dei trapianti", 25 Ciclo. DOI 10.6092/unibo/amsdottorato/5286.
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IL-33/ST2 axis is known to promote Th2 immune responses and has been linked to several autoimmune and inflammatory disorders, including inflammatory bowel disease (IBD), and recent evidences show that it can regulate eosinophils (EOS) infiltration and function. Based also on the well documented relationship between EOS and IBD, we assessed the role of IL-33-mediated eosinophilia and ileal inflammation in SAMP1/YitFc (SAMP) murine model of Th1/Th2 chronic enteritis, and we found that IL-33 is related to inflammation progression and EOS infiltration as well as IL-5 and eotaxins increase. Administering IL-33 to SAMP and AKR mice augmented eosinophilia, eotaxins mRNA expression and Th2 molecules production, whereas blockade of ST2 and/or typical EOS molecules, such as IL-5 and CCR3, resulted in a marked decrease of inflammation, EOS infiltration, IL-5 and eotaxins mRNA expression and Th2 cytokines production. Human data supported mice’s showing an increased colocalization of IL-33 and EOS in the colon mucosa of UC patients, as well as an augmented IL-5 and eotaxins mRNA expression, when compared to non-UC. Lastly we analyzed SAMP raised in germ free (GF) condition to see the microbiota effect on IL-33 expression and Th2 responses leading to chronic intestinal inflammation. We found a remarkable decrease in ileal IL-33 and Th2 cytokines mRNA expression as well as EOS infiltration in GF versus normal SAMP with comparable inflammatory scores. Moreover, EOS depletion in normal SAMP didn’t affect IL-33 mRNA expression. These data demonstrate a pathogenic role of IL-33-mediated eosinophilia in chronic intestinal inflammation, and that blockade of IL-33 and/or downstream EOS activation may represent a novel therapeutic modality to treat patients with IBD. Also they highlight the gut microbiota role in IL-33 production, and the following EOS infiltration in the intestinal mucosa, confirming that the microbiota is essential in mounting potent Th2 response leading to chronic ileitis in SAMP.

Tipologia del documento
Tesi di dottorato
De Salvo, Carlo
Dottorato di ricerca
Scuola di dottorato
Scienze mediche e chirurgiche cliniche
Settore disciplinare
Settore concorsuale
Data di discussione
16 Aprile 2013

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