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B 7 The role of Epstein-Barr virus-induced gene 3 (EBI3) cytokines IL-27 and IL-35 in bacterial inflammation

Principal investigator
Markus Neurath, Stefan Wirtz

Mentor
Wolfgang Hillen

Biological role of EBI3 related cytokines IL-27 and IL-35 in Inflammatory Immune Diseases

IL-27 and IL-35 are new members of IL-12 family of heterodimeric cytokines that share EBI3 subunit with each other. These closely related cytokines, IL-27 and IL-35 could play a role in the immunological control of bacterial infections on mucosal surfaces and gut; On the other side, disregulated immune response against bacteria of commensal mycobiota are responsible for etiopathogenesis of Chronic Inflammatory Diseases; right here IL-27/IL-35 cytokines are of great importance: they induce tolerance, but can also act in proinflammatory manner. The aim of our current project is to use different gene deficient and transgenic mice to analyze the roles of these factors in infections of invasive or non-invasive bacterial intestinal pathogenes and in IBD.

In initial studies we analyzed EBI3 and Bl6 mice in the dextrane sodium sulphate (DSS) colitis model. Miniature endoscopy and histology demonstrated that EBI3-/- mice develop more acute colitis compared to wild type controls, suggesting that IL-35 has a more significant role in colitis than IL-27. We are on the way to start experiments using Salmonella to establish the role of adaptive immune system in Salmonellosis. To overcome the intestinal epithelial barrier, many enteric pathogens have evolved ability to invade and pass the intestinal epithelium as a key initial step to establish mucosal and, subsequently, systemic infection of the host. Besides facilitating the invasion process, the interaction between invading pathogen and the host epithelium also activates a program of epithelial gene expression. High density microarray analysis has shown that EBI3 belongs to the genes that are highly upregulated in intestinal epithelial cells after infection with Salmonella typhimurium in a NF-kB dependent manner. Therefore we would like to analyze the biological function of IL-12 and IL-35 in murine infection model of S.typhimuruim. Initially oral salmonella infection model will be implemented. For this reason EBI3-/- , p28-/- and subsequent wild type controls will be infected intravenously with different doses of S.typhimuruim. Afterwards survival rate at different time points will be evaluated. Furthermore, bacterial counts in blood, lungs, spleen and liver at different time points of the disease will be determined.

Figure: EBI3-/- mice develop more severe colitis. 8-10 weeks old C57BL/6 (A) and EBI3-/- (B) mice were treated with 2,5% DSS-solution in the drinking water for 7 days. Mice were endoscopied on day 10. (C) Endoscopic scoring of colitis severity.

 

Publications

 

Presentations

September 2010 2nd Annual Retreat, Erlangen School of Molecular Communication, Kloster Banz, Bad Staffelstein, Germany
IL-33/ST2 Signalling pathways in the pathogenesis of liver fibrosis”
Talk