Étude des nouvelles cytokines interleukine-31 et interleukine-33, et de leurs récepteurs respectifs, dans la fibrose hépatique

Le foie subit divers types d agressions, ce qui déclenche une réponse inflammatoire reposant sur la mobilisation de cellules immunitaires et sur la sécrétion de cytokines. La réponse cytokinique est déterminante puisqu une réponse de type Th2 est favorable au maintien d une inflammation chronique et au développement d une fibrose. Le but de ma thèse était de déterminer si les interleukines 31 et 33, deux cytokines de type Th2 récemment caractérisées, étaient associées au processus fibreux hépatique. Nous avons démontré que l IL-33 et son récepteur ST2 sont spécifiquement surexprimés lors de la fibrose hépatique humaine et murine. L IL-31 et son récepteur IL-31RA sont également significativement surexprimés dans les foies fibreux, mais le sont encore davantage dans les foies tumoraux. De plus, nous avons montré que les cellules étoilées hépatiques activées sont une source importante d IL-33 dans les foies fibreux et nous avons donc étudié la régulation de l IL-33 dans ces cellules.Liver undergoes various attacks that promote an inflammatory response based on the mobilization of immune cells and the secretion of cytokines. The cytokine response is crucial, since a Th2-type response supports the maintenance of a chronic inflammation and the development of fibrosis. The purpose of my work was to determine whether interleukins 31 and 33, two cytokines recently characterized as Th2 cytokine, were involved in the hepatic fibrotic process. We found that IL-33 and its receptor ST2 are specifically overexpressed during human and mice liver fibrosis. IL-31 and its receptor IL-31RA are significantly overexpressed in fibrotic livers and their expressions are further increased in tumoral livers. Moreover, we have shown that activated hepatic stellate cells are an important source of IL-33 in fibrotic livers and we thus studied IL-33 regulation in these cells.RENNES1-BU Sciences Philo (352382102) / SudocSudocFranceF

Interleukin-33 overexpression is associated with liver fibrosis in mice and humans.

International audienceInterleukin-33 (IL-33), the most recently identified member of the IL-1 family, induces synthesis of T Helper 2 (Th2)-type cytokines via its heterodimeric ST2/IL-1RAcP receptor. Th2-type cytokines play an important role in fibrosis; thus, we investigated the role of IL-33 in liver fibrosis. IL-33, ST2 and IL-1RAcP gene expression was analysed in mouse and human normal (n= 6) and fibrotic livers (n= 28), and in human hepatocellular carcinoma (HCC; n= 22), using real-time PCR. IL-33 protein was detected in normal and fibrotic liver sections and in isolated liver cells using Western blotting and immunolocalization approaches. Our results showed that IL-33 and ST2 mRNA was overproduced in mouse and human fibrotic livers, but not in human HCC. IL-33 expression correlated with ST2 expression and also with collagen expression in fibrotic livers. The major sources of IL-33 in normal liver from both mice and human beings are the liver sinusoidal endothelial cells and, in fibrotic liver, the activated hepatic stellate cells (HSC). Moreover, IL-33 expression was increased in cultured HSC when stimulated by pro-inflammatory cytokines. In conclusion, IL-33 is strongly associated with fibrosis in chronic liver injury and activated HSC are a source of IL-33