123: Functional analysis of CISH (Cytokine inducible SH2-containing protein)

Abstract

Introduction The evolution of multicellular organisms has required the development of systems that allow cells to respond to external signals. Cytokine signalling represents one of these, and is involved in key biological processes, including blood and immune development as well as function. The ability to subsequently extinguish these signals is important to avoid pathogenic outcomes. The Suppressor of cytokine signalling (Socs) family of proteins represents an important mechanism to achieve this. The Cytokine Inducible SH2 domain-containing (CISH) protein was the first identified member of the Socs family. In vitro studies have suggested the involvement of CISH as a negative regulator of signalling by EPO, IL-2, GH and GCSF. Recent genetic studies have implicated CISH in the susceptibility of humans to infectious disease and mice to allergic airway inflammation, as well as for a zebrafish homologue (Cish.a) in regulating embryonic haematopoiesis. Aim This study has employed CISH targeted mice as a relevant model to further investigate the role of CISH in regulating development and disease. Methods Mice were generated from ES cells in which the Cish locus was targeted with LacZ. These have been analysed by β-galactosidase staining and histology. Results β-gal staining of Cish Lacz −/+ mice embryos revealed expression from 11.5 post-conception, continuing in adult mice, across a wide range of different organs. Among haematopoietic organs CISH expression was predominantly observed in the thymus. Among visceral organs, expression was observed in kidney, stomach and liver. CISH expression was also observed in lung, heart, and brain. Sex-specific changes in expression were noted. Conclusion CISH expression in a wide range of organs is consistent with the broad expression of other cytokine receptor signalling components, including Jak2 and Stat5a/Stat5b. Positive β-gal staining in the liver, kidneys, thymus, and brain support a regulatory role for CISH in these organs to control relevant cytokine signalling, such as by growth hormone, erythropoietin, IL-4 and IL-2, through the Jak/Stat signalling pathway.