We are studying the structure-function relationships of chemokines and their receptors. We have identified an indirect pathway by which IL-8 attracts mononuclear cells by the process of neutrophil degranulation. This results in the release of defensins 1 and 2 and CAP37/azurocidin which are also T-cell chemoattractants and the monocyte chemoattractant, cathepsin G. The biological relevance of these in vitro results were reinforced by observations that subcutaneous injections of defensins and azurocidin result in the local accumulation of inflammatory cells. Furthermore, we have found that defensins have adjuvant activities and enhance in vivo antibody responses. We have filed for a patent for the immunostimulating effects of defensins and azurocidin in conjunction with our CRADA collaborators at the Genetics Institute. A major goals of these studies is to ascertain whether these neutrophil granule products mediate the capacity of neutrophils to activate mononuclear cell responses. The proinflammatory and potential tumor promoting effects chemokines points to the need to develop potent inhibitors. We are approaching this by studying the molecular mechanisms of homologous desensitization of chemokine responses. We have shown that phosphorylation of threonine and serine residues in the cytoplasmic c-terminal domain of the IL-8RB receptor is necessary for desensitization of the response, but not for activation by the receptors. These cytoplasmic domains can be used as targets for generating inhibitors of chemotaxis. We have also initiated studies of heterologous desensitization of chemokines receptors by opioids. Opioids also utilize seven transmembrane receptors (STM) and are chemotactic. Prior exposure to metenkephalin can cross-desensitize and block subsequent monocyte and neutrophil chemotactic responses to chemokines. The possibility that this may account for anti-inflammatory effects of opioids will be studied.
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