Regulated production and molecular diversity of human liver and activation-regulated chemokine/macrophage inflammatory protein-3 alpha from normal and transformed cells

Liver and activation-regulated chemokine (LARC), also designated macrophage inflammatory protein-3 alpha (MIP-3 alpha), Exodus, or CCL20, is a C-C che mokine that attracts immature dendritic cells and memory T lymphocytes, bot h expressing CCR6. Depending on the cell type, this chemokine was found to be inducible by cytokines (IL-1 beta) and by bacterial, viral, or plant pro ducts (including LPS, dsRNA, and PMA) as measured by a specific ELISA, Alth ough coinduced with monocyte chemotactic protein-1 (MCP-1) and IL-8 by dsRN A, measles virus, and IL-1 beta in diploid fibroblasts, leukocytes produced LARC/MIP-3 alpha only in response to LPS, However, in myelomonocytic THP-1 cells LARC/MIP-3 alpha was better induced by phorbol ester, whereas in HEp -2 epidermal carcinoma cells IL-1 beta was the superior inducer. The produc tion levels of LARC/MIP-3 alpha (1-10 ng/ml) were, on the average, 10- to 1 00-fold lower than those of IL-8 and MCP-1, but were comparable to those of other less abundantly secreted chemokines, Natural LARC/MIP-3 alpha protei n isolated from stimulated leukocytes or tumor cell lines showed molecular diversity, in that NH2- and COOH-terminally truncated forms were purified a nd identified by amino acid sequence analysis and mass spectrometry, In con trast to other chemokines, including MCP-1 and IL-8, the natural processing did not affect the calcium-mobilizing capacity of LARC/MIP-3 alpha through its receptor CCR6. Furthermore, truncated natural LARC/MIP-3 alpha isoform s were equally chemotactic for lymphocytes as intact rLARC/MIP-3 alpha. It is concluded that in addition to its role in homeostatic trafficking of leu kocytes, LARC/MIP-3 alpha can function as an inflammatory chemokine during host defense.