MIC-1, a Novel Macrophage Inhibitory Cytokine, is a Divergent Member of the TGF-β superfamily

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 94; no. 21; pp. 11514 - 11519
• Main Authors: Bootcov, Michelle R., Bauskin, Asne R., Valenzuela, Stella M., Moore, Anthony G., Bansal, Mohinder, He, Xiao Yan, Zhang, Hong Ping, Donnellan, Melissa, Mahler, Stephen, Pryor, Kimberley, Walsh, Bradley J., Nicholson, Richard C., Fairlie, W. Douglas, Por, Suzanne B., Robbins, Joan M., Breit, Samuel N.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 14.10.1997; National Acad Sciences; National Academy of Sciences; The National Academy of Sciences of the USA
• Subjects: Amino Acid Sequence; Amino acids; Animals; Bacteriophages; Base Sequence; Biological Sciences; Cell Line; Cell lines; Cells, Cultured; Cellular biology; Chickens; Cytokines; Cytokines - biosynthesis; Cytokines - chemistry; Cytokines - pharmacology; Gene Library; Genes; Growth Differentiation Factor 15; Humans; Immunity (Disease); Kidney cells; Lipopolysaccharides - pharmacology; Macrophage activation; Macrophage Activation - drug effects; Macrophages; Messenger RNA; Molecular Sequence Data; Molecules; Monocytes - drug effects; Monocytes - immunology; Phylogeny; Proteins; Recombinant Proteins - biosynthesis; Recombinant Proteins - chemistry; Recombinant Proteins - pharmacology; Secretion; Sequence Alignment; Sequence Homology, Amino Acid; Transfection; Transforming Growth Factor beta - biosynthesis; Transforming Growth Factor beta - chemistry; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha - biosynthesis; Xenopus
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.94.21.11514

Macrophages play a key role in both normal and pathological processes involving immune and inflammatory responses, to a large extent through their capacity to secrete a wide range of biologically active molecules. To identify some of these as yet not characterized molecules, we have used a subtraction cloning approach designed to identify genes expressed in association with macrophage activation. One of these genes, designated macrophage inhibitory cytokine 1 (MIC-1), encodes a protein that bears the structural characteristics of a transforming growth factor β (TGF-β ) superfamily cytokine. Although it belongs to this superfamily, it has no strong homology to existing families, indicating that it is a divergent member that may represent the first of a new family within this grouping. Expression of MIC-1 mRNA in monocytoid cells is up-regulated by a variety of stimuli associated with activation, including interleukin 1β , tumor necrosis factor α (TNF-α ), interleukin 2, and macrophage colony-stimulating factor but not interferon γ , or lipopoly-saccharide (LPS). Its expression is also increased by TGF-β . Expression of MIC-1 in CHO cells results in the proteolytic cleavage of the propeptide and secretion of a cysteine-rich dimeric protein of Mr25 kDa. Purified recombinant MIC-1 is able to inhibit lipopolysaccharide -induced macrophage TNF-α production, suggesting that MIC-1 acts in macrophages as an autocrine regulatory molecule. Its production in response to secreted proinflammatory cytokines and TGF-β may serve to limit the later phases of macrophage activation.