Leukocyte recruitment and activation is a hallmark of both acute and chronic inflammatory lung disease. Although the exact mechanism(s) by which inflammatory cells are recruited to the lungs remains unknown, it is likely that the local production of inflammatory cell-specific chemotactic factors and the establishment of chemotactic gradients is of critical importance. Mononuclear phagocytes, including alveolar macrophages (AM), play a central role in leukocyte recruitment via the production of chemotactic factors, including the neutrophil/lymphocyte chemotaxin Interleukin 8 (IL-8), as well as the expression of the important proximal mediators tumor necrosis factor (TNF) and interleukin 1(IL-1). The local production of TNF and IL-1 can act in a paracrine fashion to induce the expression of IL-8 and the monocyte-specific chemotaxin monocyte chemoattractant protein-1 (MCP-1) from non-immune cellular constituents of the alveolar-capillary wall (ACW) (pulmonary endothelial cells, fibroblasts, and epithelial cells). In addition, immune-mediated lung diseases are often characterized by the influx of activated lymphocytes and their secreted products, which have been shown to significantly influence the expression of mononuclear phagocyte-derived cytokines. This investigation will focus on a mechanistic approach to assess the immunoregulatory roles of the specific lymphocyte products gamma interferon (IFN-g) and interleukin-4 (IL-4) on the modulation of pulmonary cytokine networks that lead to the elaboration of the chemotactic cytokines IL-8 and MCP-1. Initial studies will investigate the effects of IL-4 and IFN-g on the cellular and molecular regulation of TNF-a, IL-1b, and IL-8 expression from peripheral blood monocytes (PBM) and AM, as well as their effects on IL-8 and MCP-1 from non-immune cells that comprise the ACW. Additional studies will examine the regulatory effects of these lymphokines on the production of cytokines from macrophages at various stages of differentiation. Further studies are proposed to investigate the regulatory influences of IL-4 and IFN-g on in vitro systems of cytokine networking between mononuclear phagocytes and non-immune cells of the ACW that ultimately lead to the expression of chemotactic cytokines. Techniques employed to perform the above investigations include Northern blot analysis, immunohistochemistry, ELISA, and assessment of bioactivity. In addition, Nuclear transcriptional analysis, mRNA stability studies, and RNA/protein interactions will be utilized to further characterize the molecular mechanisms by which IL-4 and IFN-g regulate the expression of cytokines from immune and non-immune cells. This proposal will provide important information regarding cellular and molecular mechanisms operative in the regulation of cytokine production by specific cells of the pulmonary airspace and interstitium.
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