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

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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
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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 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.
AbstractList	Bootcov et al used a subtraction cloning approach to identify genes expressed in association with macrophage activation. One of these genes, macrophage inhibitory cytokine 1 (MIC-1), encodes a protein that bears the structural characteristics of a transforming growth factor beta superfamily cytokine. 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 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 M r 25 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. 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. 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 1 beta , 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 M sub(r) 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. 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. 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 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 M r 25 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.
Author	Bootcov, Michelle R. Zhang, Hong Ping Donnellan, Melissa Fairlie, W. Douglas Valenzuela, Stella M. Pryor, Kimberley Walsh, Bradley J. Bauskin, Asne R. Bansal, Mohinder Mahler, Stephen He, Xiao Yan Por, Suzanne B. Nicholson, Richard C. Breit, Samuel N. Moore, Anthony G. Robbins, Joan M.
AuthorAffiliation	Centre for Immunology, St. Vincent’s Hospital, and University of New South Wales, Sydney, 2010, Australia; and ‡ Department of Biotechnology, University of New South Wales, Sydney, 2010, Australia
AuthorAffiliation_xml	– name: Centre for Immunology, St. Vincent’s Hospital, and University of New South Wales, Sydney, 2010, Australia; and ‡ Department of Biotechnology, University of New South Wales, Sydney, 2010, Australia
Author_xml	– sequence: 1 givenname: Michelle R. surname: Bootcov fullname: Bootcov, Michelle R. – sequence: 2 givenname: Asne R. surname: Bauskin fullname: Bauskin, Asne R. – sequence: 3 givenname: Stella M. surname: Valenzuela fullname: Valenzuela, Stella M. – sequence: 4 givenname: Anthony G. surname: Moore fullname: Moore, Anthony G. – sequence: 5 givenname: Mohinder surname: Bansal fullname: Bansal, Mohinder – sequence: 6 givenname: Xiao Yan surname: He fullname: He, Xiao Yan – sequence: 7 givenname: Hong Ping surname: Zhang fullname: Zhang, Hong Ping – sequence: 8 givenname: Melissa surname: Donnellan fullname: Donnellan, Melissa – sequence: 9 givenname: Stephen surname: Mahler fullname: Mahler, Stephen – sequence: 10 givenname: Kimberley surname: Pryor fullname: Pryor, Kimberley – sequence: 11 givenname: Bradley J. surname: Walsh fullname: Walsh, Bradley J. – sequence: 12 givenname: Richard C. surname: Nicholson fullname: Nicholson, Richard C. – sequence: 13 givenname: W. Douglas surname: Fairlie fullname: Fairlie, W. Douglas – sequence: 14 givenname: Suzanne B. surname: Por fullname: Por, Suzanne B. – sequence: 15 givenname: Joan M. surname: Robbins fullname: Robbins, Joan M. – sequence: 16 givenname: Samuel N. surname: Breit fullname: Breit, Samuel N.
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/9326641$$D View this record in MEDLINE/PubMed
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Snippet	Macrophages play a key role in both normal and pathological processes involving immune and inflammatory responses, to a large extent through their capacity to... Bootcov et al used a subtraction cloning approach to identify genes expressed in association with macrophage activation. One of these genes, macrophage...
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SubjectTerms	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
Title	MIC-1, a Novel Macrophage Inhibitory Cytokine, is a Divergent Member of the TGF-β superfamily
URI	https://www.jstor.org/stable/43317 http://www.pnas.org/content/94/21/11514.abstract https://www.ncbi.nlm.nih.gov/pubmed/9326641 https://www.proquest.com/docview/201347851 https://search.proquest.com/docview/16118625 https://search.proquest.com/docview/79327014 https://pubmed.ncbi.nlm.nih.gov/PMC23523
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