Cytokines and host defence peptides: Delineating molecular mechanisms regulating inflammation

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Molecules known as cytokines are critical in orchestrating immune responses. An important element of immunity is the process of inflammation, which is normally self-limiting and tightly regulated. A breakdown in the regulation of this process results in inappropriately excessive and sustained inflammation. A common element in inflammation is the elevated levels of certain cytokines. Abnormally elevated levels of some of these cytokines are known to amplify the process of inflammation. Recent studies have shown that small natural peptides, known as host defence peptides (HDPs), may be important in regulation of inflammation. Our previous research has shown that these HDPs can exhibit an overall anti-inflammatory effect. However, how HDPs regulate cytokine induced cellular responses in inflammation is poorly understood. Therefore, our research focus is to understand how HDPs alter or regulate cytokine-activated processes in inflammation. The short term i.e. 5 year research goal is to focus on a well defined human HDP, known as cathelicidin LL-37. We have previously shown that LL-37 can suppress inflammation in the presence of an infection or tissue injury. However, the function of LL-37 in the presence of inflammatory cytokines is not understood. We will study the molecular processes of how LL-37 may alter the effect of two inflammatory cytokines in our 5 year goal. In order to facilitate our research objectives, we will determine the proteins and enzymes that are activated by inflammatory cytokines, and how these responses change in the presence of HDPs such as LL-37. We will study these molecular mechanisms in two different cell types, in immune cells and in structural stromal cells which are the connective tissue cells of any organ. Our long term overall goal is to determine the effects of HDPs in inflammatory cytokine-induced cellular processes. Overall, our studies will provide a broader understanding of the impact of the endogenous HDP molecules on cellular processes that are important for regulation of inflammation.