Dissertation (Metadaten)
Titel:Generation of sgp130Fc transgenic mice: Inhibition of IL-6-transsignaling in vivo impairs the proper resolution of acute inflammation
Autor:Björn Rabe
Fakultät:Mathematisch-Naturwissenschaftliche Fakultät
DDC Sachgebiet:570 Biowissenschaften, Biologie
Datum der mdl. Prüfung:26.04.2007
Referent(in):Prof. Dr. Dr. T. Bosch
Korreferent(en) Korreferentin:Prof. Dr. S. Rose-John
Beschreibung:Interleukin 6 (IL6) cytokine signaling is based on classic and trans-signaling. Classic signaling utilizes the membrane bound Interleukin 6 receptor (IL6R), whereas in trans-signaling IL6 acts via a soluble form of the IL6 receptor. The signal transducing subunit gp130 of the IL6 receptor complex is ubiquitously expressed whereas the IL6R is only sparely expressed. The specific occurrence of the soluble IL6R (sIL6R) during acute and chronic inflammation massively increases the number of target cells for IL6. To address the question whether IL6 trans-signaling is important in vivo transgenic mice were generated, which overexpress the soluble designer receptor antagonist sgp130Fc. To achieve high level accumulation of the sgp130Fc protein in vivo a cDNA-optimization strategy (opt_sgp130Fc) was applied. These mice displayed an IL6-trans-signaling knock out phenotype, since sgp130Fc specifically inhibits only IL6 trans-signaling but not classic IL6 signaling. The transgenic mice are resistant to the IL6/sIL6R-mediated induction of acute phase response. Furthermore, it was shown that during acute inflammation the recruitment of mononuclear cells is strictly dependent on IL6 trans-signaling. The soluble IL6 receptor is released from activated neutrophils at the site of inflammation and in complex with IL6 induces a chemokine expression pattern, which leads to subsequent infiltration of mononuclear cells, and which is specifically blocked in opt_sgp130Fc transgenics.
Schlagworte:IL-6-transsignaling, sgp130Fc, transgenic mice, soluble IL-6R, acute inflammation
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