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The Journal of Immunology, 2000, 165: 4470-4477.
Copyright © 2000 by The American Association of Immunologists

Regulated Production and Molecular Diversity of Human Liver and Activation-Regulated Chemokine/Macrophage Inflammatory Protein-3{alpha} from Normal and Transformed Cells1

Evemie Schutyser, Sofie Struyf, Patricia Menten, Jean-Pierre Lenaerts, René Conings, Willy Put, Anja Wuyts, Paul Proost and Jo Van Damme2

Laboratory of Molecular Immunology, Rega Institute for Medical Research, University of Leuven, Leuven, Belgium

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-1ß) 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-1ß 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-1ß 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.




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