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

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 beta (TGF-beta) 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 1beta, tumor necrosis factor alpha (TNF-alpha), interleukin 2, and macrophage colony-stimulating factor but not interferon gamma, or lipopolysaccharide (LPS). Its expression is also increased by TGF-beta. 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 macrophage TNF-alpha production, suggesting that MIC-1 acts in macrophages as an autocrine regulatory molecule. Its production in response to secreted proinflammatory cytokines and TGF-beta may serve to limit the later phases of macrophage activation.

Pubmed ID: 9326641

Authors

  • Bootcov MR
  • Bauskin AR
  • Valenzuela SM
  • Moore AG
  • Bansal M
  • He XY
  • Zhang HP
  • Donnellan M
  • Mahler S
  • Pryor K
  • Walsh BJ
  • Nicholson RC
  • Fairlie WD
  • Por SB
  • Robbins JM
  • Breit SN

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Data

October 14, 1997

Associated Grants

None

Mesh Terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Cell Line
  • Cells, Cultured
  • Chickens
  • Cytokines
  • Gene Library
  • Growth Differentiation Factor 15
  • Humans
  • Lipopolysaccharides
  • Macrophage Activation
  • Molecular Sequence Data
  • Monocytes
  • Phylogeny
  • Recombinant Proteins
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Transfection
  • Transforming Growth Factor beta
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha
  • Xenopus