To understand phagocyte activation processes, we previously cloned cDNAs for the following G protein-coupled chemotactic receptors: the N- formylpeptide receptor, interleukin-8 receptor type B (an alpha chemokine receptor), and the MIP-1alpha/RANTES receptor (a beta chemokine receptor, also known as CC CKR1). We also previously established that open reading frame ECRF3 of Herpesvirus saimiri encodes an interleukin-8 receptor. We have now characterized the first potent non-formylated synthetic peptide agonist for the N-formylpeptide receptor, breaking a longstanding structural constraint for the consideration of natural agonists for the receptor. Our work on chemokine receptors has led to the following recent discoveries. 1) We established that open reading frame US28 of human cytomegalovirus encodes a beta chemokine receptor most selective for RANTES. 2) We cloned the first eosinophil-selective beta chemokine receptor, designated CC CKR3. Its agonist rank order is MIP- 1alpha>RANTES>MIP-1beta. 3) We showed that in addition to MIP-1alpha and RANTES, MCP-3 is also a potent agonist for CC CKR1. CC CKR1 is the first receptor cloned for MCP-3. 4) CC CKR1 is highly expressed in monocytes, neutrophils, placenta, liver and lung. CC CKR2B is an MCP-1 receptor selectively expressed in monocytes, lung and liver. 5) We cloned a gene for a related orphan receptor CMKBRL1 that is selectively expressed in brain, neutrophils and monocytes. 6) We identified a mouse gene cluster on chromosome 9 that contains three genes related to the human genes for CC CKR1 and CC CKR3, and showed that a third related human gene probably does not exist. All three mouse genes are expressed in leukocytes, but are differentially expressed in mouse solid organs, suggesting novel targets for beta chemokine action. Two of the genes are currently orphans, the third encodes the first functional mouse beta chemokine receptor to be cloned. Its only known agonist is MIP-1alpha. 7) Finally, we established the gene organization and promoter function for interleukin-8 receptors A and B. Our work indicates profound complexity in the molecular apparatus that mediates phagocyte chemotaxis. Our discovery of differential expression of chemokine receptors in phagocytes suggests they may be responsible for selective phagocyte accumulation in pathological states, making them good targets for development of cell type-selective anti-inflammatory drugs. Our discovery of two viral chemokine receptors points to new ways for studying how herpesviruses infect their hosts and evolve with them.
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