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-3alpha (MIP-3alpha), 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-1beta) 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-1beta in diploid fibroblasts, leukocytes produced LARC/MIP-3alpha only in response to LPS. However, in myelomonocytic THP-1 cells LARC/MIP-3alpha was better induced by phorbol ester, whereas in HEp-2 epidermal carcinoma cells IL-1beta was the superior inducer. The production levels of LARC/MIP-3alpha (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-3alpha protein isolated from stimulated leukocytes or tumor cell lines showed molecular diversity, in that NH(2)- 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-3alpha through its receptor CCR6. Furthermore, truncated natural LARC/MIP-3alpha isoforms were equally chemotactic for lymphocytes as intact rLARC/MIP-3alpha. It is concluded that in addition to its role in homeostatic trafficking of leukocytes, LARC/MIP-3alpha can function as an inflammatory chemokine during host defense.
Schutyser
E
E
Laboratory of Molecular Immunology, Rega Institute for Medical Research, University of Leuven, Leuven, Belgium.
Struyf
S
S
Menten
P
P
Lenaerts
J P
JP
Conings
R
R
Put
W
W
Wuyts
A
A
Proost
P
P
Van Damme
J
J
D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D054418:Chemokine CCL20; D019742:Chemokines, CC / Q000096:biosynthesis* / Q000737:chemistry / Q000302:isolation & purification* / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D004171:Diploidy; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis* / Q000737:chemistry / Q000302:isolation & purification* / Q000502:physiology; D020033:Protein Isoforms / Q000096:biosynthesis / Q000737:chemistry / Q000302:isolation & purification / Q000502:physiology; D054399:Receptors, CCR6; D019707:Receptors, Chemokine; D011971:Receptors, Immunologic / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology; D014407:Tumor Cells, Cultured
C108355:CCL20 protein, human; C106311:CCR6 protein, human; D054418:Chemokine CCL20; D019742:Chemokines, CC; D019402:Macrophage Inflammatory Proteins; D020033:Protein Isoforms; D054399:Receptors, CCR6; D019707:Receptors, Chemokine; D011971:Receptors, Immunologic