Grant: Doctoral Award - Frederick Banting and Charles Best Canada Graduate Scholarships

Inflammation is a protective response against infection but it must be appropriately controlled and terminated to avoid pathological consequences. A key anti-inflammatory regulator of immune cells is a cytokine (a type of hormone) called interleukin-10 (IL-10). The importance of IL-10 in regulating immune cell function is illustrated by the fact that many tumour cells and intracellular pathogens produce or elicit production of IL-10 to enhance their survival. Thus, understanding the mechanism by which IL-10 regulates the network of intracellular signal transduction pathways will not only provide insight into development of therapeutics mimicking the beneficial, anti-inflammatory effects of IL-10, it will also allow development of strategies to counter the immunosuppressive effects of certain tumours and immune cell pathogens. Recent research shows that IL-10 may, in part, regulate immune cell function through altering the amount of small RNAs (microRNAs, abbreviated miRNA) found in cells. There are approximately 1000 different miRNAs in the mammalian genome, each of which controls a specific network of genes. Stimulation of immune cells such as the macrophage with bacteria (or with substances found on the surface of bacteria) leads to changes in the levels of certain miRNAs. We have found that IL-10 counteracts some of these changes, and may indeed induce some specific changes that are important in IL-10 inhibition of cell activation. One miRNA of particular interest is miR-155. We now propose i) to continue to investigate how IL-10 regulates miR-155 levels, ii) to systematically identify all the miRNAs whose levels change in cells treated with IL-10, and iii) to determine the contribution of each miRNA to the ability of IL-10 to inhibit inflammation. These studies will lead to a better understanding of how IL-10 works and the knowledge can be used to develop miRNA-based therapeutic strategies to mimic or inhibit IL-10 action when needed.