Regulated production and molecular diversity of human liver and activation-regulated chemokine/macrophage inflammatory protein-3α 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 chemokine that attracts immature dendritic cells and memory T lymphocytes, both 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 products (including LPS, dsRNA, and PMA) as measured by a specific ELISA, Although coinduced with monocyte chemotactic protein-1 (MCP-1) and IL-8 by dsRNA, 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 production levels of LARC/MIP-3 alpha (1-10 ng/ml) were, on the average, 10- to 100-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 protein isolated from stimulated leukocytes or tumor cell lines showed molecular diversity, in that NH2- and COOH-terminally truncated forms were purified and identified by amino acid sequence analysis and mass spectrometry, In contrast 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 isoforms were equally chemotactic for lymphocytes as intact rLARC/MIP-3 alpha. It is concluded that in addition to its role in homeostatic trafficking of leukocytes, LARC/MIP-3 alpha can function as an inflammatory chemokine during host defense.