MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-β superfamily

Michelle R. Bootcov, Asne R. Bauskin, Stella M. Valenzuela, Anthony G. Moore, Mohinder Bansal, Xiao Yan He, Hong Ping Zhang, Melissa Donnellan, Stephen Mahler, Kimberley Pryor, Bradley J. Walsh, Richard C. Nicholson, W. Douglas Fairlie, Suzanne B. Por, Joan M. Robbins, Samuel N. Breit*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

750 Citations (Scopus)

Abstract

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 18 (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 lipopolysaccharide (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 Mr 25 kDa. Purified recombinant MIC-1 is able to inhibit lipopolysaccharide -induced macrophase TNF-α production, suggesting that MIC-1 acts in macro-phases as an autocrine regulatory molecule. Its production in response to secreted proinflammatory cytokines and TGF-β may serve to limit the later phases of macrophase activation.

Original languageEnglish
Pages (from-to)11514-11519
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume94
Issue number21
DOIs
Publication statusPublished - 14 Oct 1997
Externally publishedYes

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