Genomic organization and biological characterization of the novel human CCchemokine DC-CK-1/PARC/MIP-4/SCYA18

The chemokines are a group of chemotactic molecules that appear to regulate the directed movement of white blood cells in vitro and in vivo and may th erefore play important roles in inflammation and immunity. The genes encodi ng the chemokines are clustered in close physical proximity to each other. A large cluster of human CC chemokine genes resides on chromosome 17, We ha ve used this information in a positional cloning approach to identify novel chemokine genes within this cluster. We constructed a YAC contig encompass ing the MIP-1 alpha (HGMW-approved symbol SCYA3) gene region and used exon trapping and sequence analysis to isolate novel chemokine genes. Using this approach, a gene encoding a chemokine named MIP-4, based on its homology w ith MIP-1 alpha (49.5% identity at the nucleotide level and 59.6% at the pr edicted amino acid level), was found. The MIP-4 gene (HGMW-approved symbol SCYA18) consists of three exons spread over 7.1 kb and is separated from th e MIP-1 alpha gene by 16 kb. The MIP-4 gene encodes a 750-bp mRNA that is e xpressed in lung and macrophages but not in brain or muscle, The mRNA encod es an 89-amino-acid protein and includes a predicted signal peptide of 21 a mino acids, Recombinant or synthetic MIP-4 induced calcium mobilization in naive and activated T lymphocyte subpopulations in vitro. Injection of synt hetic MIP-4 into the peritoneal cavity of mice led to the accumulation of b oth CD4(+) and CD8(+) T lymphocytes, but not monocytes or granulocytes. The se observations provide new information concerning the arrangement of the C C chemokine gene cluster on human chromosome 17 and indicate that the MIP-4 gene product is chemotactic in vivo for both CD4(+) and CD8(+) T lymphocyt es and may therefore be implicated in both humoral and cell-mediated-immuni ty, (C) 1999 Academic Press.