THE INHIBITION OF INFLAMMATORY PROCESSES

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The goal of this study is to identify mechanisms of viral inhibition of inflammation. This information should enhance our understanding of both the regulation of specific inflammatory responses, and the role of specific mediators of these responses. Cowpox virus, a DNA-containing virus encoding about two hundred gene products, is capable of inhibiting mammalian inflammatory responses against virus infection. Because of this property, it provides a unique system for the investigation of inflammatory processes. This system has already enabled us to identify two novel inhibitors of inflammatory mediators: an inhibitor of the IL-1beta maturase, and a secreted TNFalpha-binding protein. These two viral proteins are not sufficient to inhibit inflammatory responses, even though the two cytokine targets of the inhibitors are pivotal mediators of inflammation. The two inhibitors must act with other viral proteins to inhibit the multiple inflammatory processes. The specific aims of this study are: 1. To identify each of the viral proteins contributing to the inhibition of inflammatory responses. 2. To characterize the anti-inflammatory proteins and the processes they inhibit. 3. To determine the mechanisms by which the viral proteins inhibit inflammatory processes. Standard genetic and biochemical procedures will be used to achieve these aims, taking advantage of the special properties of this biological system, including the ease with which the genetic composition of these viruses can be modified. Knowledge of the mechanisms involved in this effective viral inhibition of inflammatory responses should assist the development of novel methods to manage both acute and chronic inflammation.