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.
Bootcov
M R
MR
Centre for Immunology, St. Vincent's Hospital, and University of New South Wales, Sydney, 2010, Australia.
Bauskin
A R
AR
Valenzuela
S M
SM
Moore
A G
AG
Bansal
M
M
He
X Y
XY
Zhang
H P
HP
Donnellan
M
M
Mahler
S
S
Pryor
K
K
Walsh
B J
BJ
Nicholson
R C
RC
Fairlie
W D
WD
Por
S B
SB
Robbins
J M
JM
Breit
S N
SN
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
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