Negative regulation of cytokine signaling in inflammation
The regulation of haematopoiesis involves intricate communication between blood cells and their environment. Cytokines are proteins that act as messengers between cells, influence the proliferation, survival, maturation and functional activation of blood cells. These blood cell “hormones” are crucial in maintaining appropriate cell numbers and ensuring effective cell function. The positive influences of cytokines must be balanced by mechanisms to prevent excessive responses. Over the last decade, the Laboratory has used gene knockout technology to define the biological roles of the Suppressors of Cytokine Signalling (SOCS), a family of proteins that attenuate cellular cytokine responses to cytokines. In collaboration with Doug Hilton in the Division of Molecular Medicine and the other Laboratory Heads within the Cancer and Haematology Division, we have established that SOCS1 is an indispensable regulator of interferon responses, ensuring that the beneficial immune effects of this cytokine can be manifest without collateral damage to healthy tissues. Similarly, SOCS3 regulate responses to the clinically important cytokine G-CSF and, along with controlling interleukin-6 (IL-6), is essential to prevent spontaneous inflammatory disease.
Our current studies are focused on understanding the cellular basis for the essential role SOCS3 plays in preventing inflammatory disease in vivo. We have shown that SOCS3 is essential within the blood cells themselves to prevent excess production of specialized inflammatory cells called neutrophils and to ward of pathological inflammation, but expression in other cell types or tissues seems also to be important. Identifying these other cells and understanding how deficiency of SOCS3 perturbs the development of neutrophils is an important priority.
Within the SOCS protein family, 4 members: SOCS1, SOCS2, SOCS3 and CIS, have structural similarities and are implicated in regulating similar cytokines. This raises the possibility that SOCS proteins may act in concert to regulate cytokine responses. To determine whether there are shared or overlapping physiological roles of SOCS-1, SOCS2, SOCS-3 and CIS, we are examining cytokine responses and inflammation in the absence of functional genes for 2 or more of these proteins. As key regulators of inflammatory cytokines, defining the specific biological roles of the SOCS proteins will inform potential use of SOCS proteins or their inhibitors in inflammatory disease.