HCC-2, A HUMAN CHEMOKINE - GENE STRUCTURE, EXPRESSION PATTERN, AND BIOLOGICAL-ACTIVITY

Cloning and sequencing of the upstream region of the gene of the CC ch emokine HCC-1 led to the discovery of an adjacent gene coding for a CC chemokine that was named ''HCC-2.'' The two genes are separated by 12 -kbp and reside in a head-to-tail orientation on chromosome 17. At var iance with the genes for HCC-1 and other human CC chemokines, which ha ve a three-exon-two-intron structure, the HCC-2 gene consists of four exons and three introns. Expression of HCC-2 and HCC-1 as studied by N orthern analysis revealed, in addition to the regular, monocistronic m RNAs, a common, bicistronic transcript. In contrast to HCC-1, which is expressed constitutively in numerous human tissues, HCC-2 is expresse d only in the gut and the liver. HCC-2 shares significant sequence hom ology with CK beta 8 and the murine chemokines C10, CCF18/MRP-2, and m acrophage inflammatory protein 1 gamma, which all contain six instead of four conserved cysteines. The two additional cysteines of HCC-2 for m a third disulfide bond, which anchors the COOH-terminal domain to th e core of the molecule. Highly purified recombinant HCC-2 was tested o n neutrophils, eosinophils, monocytes, and lymphocytes and was found t o exhibit marked functional similarities to macrophage inflammatory pr otein la. It is a potent chemoattractant and inducer of enzyme release in monocytes and a moderately active attractant for eosinophils. Dese nsitization studies indicate that HCC-2 acts mainly via CC chemokine r eceptor CCR1.