Regulation of Chemokine Expression In Vivo

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DESCRIPTION (provided by the applicant): Inflammation following tissue injury is an essential process that protects the organism against challenge by environmental pathogens and orchestrates the restoration of tissue architecture and homeostasis. A major aspect of this activity is dependent upon the sequential infiltration of inflammatory neutrophils and monocytes that is regulated, in part, by the production of chemoattractant cytokines or chemokines. Studies conducted in cultured cell lines have demonstrated that many cell types are capable of producing chemokines in response to a broad spectrum of agents. Our laboratory and others have demonstrated that chemokine expression is regulated through cell type- and stimulus-specific alterations in transcription and mRNA stability that depend upon specific nucleotide regulatory sequences in DNA and mRNA present in individual chemokine genes. Recent findings from our laboratory show that chemokine expression in vivo occurs in a complex multiphase pattern that is likely to involve the participation of distinct cell types and stimuli in a temporally ordered fashion. We cannot, however, accurately predict which individual stimuli, cell types, and mechanisms are responsible for the pattern of chemokine gene expression seen in any given inflammatory setting. The overall goal of this proposal, therefore, is to determine how the regulatory mechanisms identified from our cell culture models translate into the complex pattern of cell type- and stimulus-specific chemokine gene expression observed in vivo. This will be accomplished with two experimental objectives. 1. We will use mouse models of surgical injury or contact hypersensitivity in the skin to determine (a) the primary responding cell populations in each phase of response and (b) the pro-inflammatory and/or anti-inflammatory mediators responsible for regulating expression of KC and MIP-2 chemokine genes. 2. We will use transgenic mice expressing reporter transgenes containing wild type or mutant versions of defined regulatory sequences to determine their importance in controlling cell type- and stimulus-specific chemokine gene transcription and mRNA stability in vivo.