INTERLEUKIN 8 AND ACUTE PULMONARY INFLAMMATION

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IL-8 is a chemokine produced during the inflammatory response. It has been detected in acute and chronic inflammatory diseases including acute respiratory distress syndrome, cystic fibrosis, chronic bronchitis and rheumatoid arthritis. The evidence is increasing that IL-8 is not only present, but a major causative agent for leukocyte infiltration during the inflammatory response. Because IL-8 attracts PMNs into an area of inflammation, it becomes important to understand how IL-8 interacts with its two neutrophilic receptors on the molecular level. Clear definition of the receptor and ligand structures that account for high affinity binding of IL-8 is necessary. More than one region on IL-8 appears to bind to each of the two receptors which should be reflected in more than one binding site on each receptor. In order to define the sites on the IL-8 A and B receptors that are involved in high affinity ligand binding, mutated receptor constructs - both loop exchange and selected point mutations - will be assessed for their ligand binding affinity and their functional capacity following transfection into HL60 cells. The combination of these studies with ongoing studies on IL-8 itself should provide clear definition of the complex interaction of IL-8 with its two receptors. This analysis will shed light on the field of receptor structure/function. Eventually knowledge of these specific sites of ligand/receptor interaction will provide a foundation for rationale approaches to develop inhibitory reagents by developing steric mimics of these regions. In the meantime antibodies have been produced to rabbit IL-8 A and B receptors that block IL-8 interaction with both receptors. These will be used to evaluate the role of IL-8 in leukocyte participation in a rabbit model of pulmonary inflammation.