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 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, cathepsin G or azurocidin result in the local accumulation of inflammatory cells. Furthermore, we have found that defensins and cathepsin G each have adjuvant activities and enhance in vivo antibody responses. We are currently identifying the receptor (s) for cathepsin G. 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 of chemokines points to the need to develop potent inhibitors. We are approaching this by studying the molecular mechanisms of desensitization of chemokine responses. We have 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-phosphorylate and block subsequent monocyte and neutrophil chemotactic responses to chemokines. This may account for anti-inflammatory effects of opioids. Furthermore, we have documented that gp120 and gp41 from various strains of HIV-1 can down-regulate and internalize a number of the chemokine receptors as well as the FMLP receptor. As a result, human monocytes and T cells, have reduced chemotactic responses to these stimuli, suggesting that HIV-1 envelope proteins disarm host inflammatory responses by this pathway. Based on the report that some C-C chemokines can interfere with invasion of cells via chemokine coreceptors, we established that a distamycin analogue known to prevent HIV-1 cell entry dies so by selectively interfering with ligand-receptor interaction of CCR5 and CXCR4. AIDS TITLE: Role of chemokines in resistance to HIV-1.
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