title: MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-beta superfamily.
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 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.
authors.affiliation: Centre for Immunology, St. Vincent's Hospital, and University of New South Wales, Sydney, 2010, Australia.
authors.forename: M R
authors.initials: MR
authors.lastname: Bootcov
authors.forename: A R
authors.initials: AR
authors.lastname: Bauskin
authors.forename: S M
authors.initials: SM
authors.lastname: Valenzuela
authors.forename: A G
authors.initials: AG
authors.lastname: Moore
authors.forename: M
authors.initials: M
authors.lastname: Bansal
authors.forename: X Y
authors.initials: XY
authors.lastname: He
authors.forename: H P
authors.initials: HP
authors.lastname: Zhang
authors.forename: M
authors.initials: M
authors.lastname: Donnellan
authors.forename: S
authors.initials: S
authors.lastname: Mahler
authors.forename: K
authors.initials: K
authors.lastname: Pryor
authors.forename: B J
authors.initials: BJ
authors.lastname: Walsh
authors.forename: R C
authors.initials: RC
authors.lastname: Nicholson
authors.forename: W D
authors.initials: WD
authors.lastname: Fairlie
authors.forename: S B
authors.initials: SB
authors.lastname: Por
authors.forename: J M
authors.initials: JM
authors.lastname: Robbins
authors.forename: S N
authors.initials: SN
authors.lastname: Breit
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002478:Cells, Cultured; D002645:Chickens; D016207:Cytokines / Q000096:biosynthesis* / Q000737:chemistry / Q000494:pharmacology; D015723:Gene Library; D055436:Growth Differentiation Factor 15; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects*; D008969:Molecular Sequence Data; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D010802:Phylogeny; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000494:pharmacology; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000096:biosynthesis* / Q000737:chemistry; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014981:Xenopus
chemical_list: D016207:Cytokines; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha