The role of SOCS3 and related proteins in inflammatory processes

© 2011 Dr. Hiu KiuThis thesis investigates two functional aspects of SOCS3 in inflammation: (1) the physiological role of SOCS3 in the non-haemopoietic compartment, with particular interest in endothelial cells; and (2) whether there is functional overlap between SOCS3 and SOCS1, SOCS2 and CIS in regulation of cytokine signaling. In vivo mouse models were integral to both studies. The former study employed endothelial-specific Cre transgenic mice to generate and study mice with SOCS3-deficient endothelium. To investigate whether there are shared and overlapping functions within the SOCS family, the latter study focused on characterization of double knockout mice with pair-wise deletion of SOCS3 and SOCS1, SOCS2 or CIS in hematopoietic cells. Although SOCS2 had previously been reported to regulate SOCS3 expression, this thesis demonstrates that there is no physiological role for SOCS2 in the regulation of SOCS3 protein expression and activity in primary hematopoietic cells. With this clarification, examination of mice with additional SOCS2 deletion demonstrated accelerated inflammatory disease onset in mice with haemopoietic-specific SOCS3 deficiency. Analyses of mice lacking both SOCS3 and SOCS1 and SOCS3 and CIS also revealed accelerated mortality in comparison to the single knockout mice. While the pathology observed in each of the double knockout mice, particularly in SOCS2/SOCS3 and CIS/SOCS3 double deficient mice, resembled that of the single mutants, neither G-CSF nor IL-6 signalling dysregulation in SOCS3-deficient cells was augmented in double-deficient cells. As a miscellany of haemopoietic alterations were observed in each of the double deficient mice, other mechanisms must be also involved and underpin the bases of acceleration of the disease in these mice. Further studies will be required to define which signaling pathways are involved. Collectively, this is the first in vivo study that demonstrates functional interaction among SOCS family proteins in modulation of inflammation