Mechanisms of DiseaseConcentration in plasma of macrophage inhibitory cytokine-1 and risk of cardiovascular events in women: a nested case-control study
Introduction
macrophage inhibitory cytokine 1 (MIC-1) is part of the transforming growth factor-β (tgf-β) superfamily, and it was first cloned on the basis of its increased mRNA expression associated with macrophage activation.1 Although MIC-1 is not expressed in resting macrophages, stimulation of these macrophages by several biological mediators, including tumour necrosis factor α, interleukin 1, and macrophage-colony stimulating factor, induce its expression. Because of its induction by many proinflammatory cytokines, but failure of direct induction by lipopolysaccharide and interferon γ, researchers have postulated that MIC-1 could be an autocrine downregulator of macrophage activation.1
Although originally identified in activated macrophages, MIC-1 can be expressed in several tissues.2, 3, 4, 5 Results of northern-blot analysis of human tissues show presence of small amounts of MIC-1 mRNA in kidney, pancreas, and prostate, but large amounts in placenta.2, 4 Large amounts of MIC-1 have also been detected by immunohistochemistry in biopsy specimens of breast, colon, and prostate cancer,5 but MIC-1 cannot be detected within normal epithelial cells of these organs.5 This fact, together with induction of MIC-1 expression by p53, and data showing that MIC can induce apoptosis of some epithelial tumour cell lines,6, 7, 8 also suggests a role for MIC-1 in epithelial neoplasms.
Shortly after cloning of MIC-1 cDNA, two allelic forms of this gene—due to one nucleotide polymorphism—were identified. This polymorphism causes an alteration of a histidine (H) to an aspartic acid (D) residue at position 6 of MIC-1.9 The homozygous D allele is present in about 5% of normal individuals.10 Because properties of these aminoacids differ from each other, this polymorphism could alter function of MIC-1.
While doing epitope-mapping studies of a series of monoclonal and polyclonal antibodies against MIC-1, it became apparent that one of these antibodies could discriminate between H and D alleles of MIC-1,9 a property that facilitates deduction of genotype from phenotype of MIC-1 present in serum.10 These antibodies have also enabled development of a sensitive immunoassay capable of quantification of MIC-1 in normal and pathological sera.2
Because MIC-1 is a product of activated macrophages, its concentration in serum or plasma could be useful in diagnosis of atherosclerosis. Results of studies have suggested that activated macrophages are implicated in pathogenesis of atherosclerosis and in vascular occlusion, which is often the ultimate endpoint of this process.11, 12 There are also strong epidemiological data linking measurement of inflammatory markers such as C-reactive protein and interleukin 6 with risk of vascular occlusive events.13, 14
We therefore postulated that the increased inflammatory response present within atherosclerotic vessel walls is associated with increased secretion and release of MIC-1, and that this increase in baseline concentration might be associated with increased risk of future cardiovascular events. We also aimed to assess whether any effect of plasma MIC-1 concentration on vascular risk might be modified by the H/D variation within MIC-1.
Section snippets
Participants
We did a prospective, nested, case-control study in apparently healthy women participating in the Women's Health Study (WHS), a continuing primary prevention trial of aspirin and vitamin E being done in 27 628 American women aged 45 years and older, who have no previous evidence of cardiovascular disease or cancer.15 Every study participant provided a baseline plasma and buffy-coat sample, which was stored on liquid nitrogen until time of analysis. Methods used for collection, storage, and
Results
Of 257 incident cardiovascular events assessed, 111 were myocardial infarction, 113 thromboembolic stroke, and 33 death from cardiovascular event. Women who subsequently developed these events during follow-up (cases) were more likely than their matched controls to have a history of hyperlipidaemia, hypertension, obesity, or diabetes. Use of hormone replacement therapy did not differ between groups. Because of the study design, cases and controls were almost identical in terms of age and
Discussion
Our results show that baseline concentrations of MIC-1 were raised in participants at increased risk of developing future cardiovascular events. Women with the highest concentrations of MIC-1 at entry had a risk of future myocardial infarction, thromboembolic stroke, or cardiovascular death nearly three times higher than that of women with lower concentrations. Although MIC-1 concentrations correlated with both interleukin 6 and C-reactive protein (two other inflammatory biomarkers known to
GLOSSARY
- macrophage inhibitory cytokine 1
- A member of the transforming growth factor-β (TGF-β) superfamily.
- transforming growth factor-β (tgf-β) superfamily
- Consists of several dimeric proteins having a conserved cysteine knot structure. These cytokines are typically involved in embryogenesis, regulation of growth and inflammation, and wound and fracture healing. This superfamily contains proteins such as TGF-β, bone morphogenetic proteins, inhibins, and glial-derived neurotrophic factors.
- p21
- A universal
References (21)
- et al.
Placental transforming growth factorbeta is a downstream mediator of the growth arrest and apoptotic response of tumor cells to DNA damage and p53 overexpression
J Biol Chem
(2000) - et al.
Profile of gene expression regulated by induced p53: connection to the TGF-beta family
FEBS Lett
(2000) - et al.
Antioxidant properties of macrophages toward low-density lipoprotein
Trends Cardiovasc
(2001) - et al.
MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-beta superfamily
Proc Natl Acad Sci USA
(1997) - et al.
The transforming growth factor-beta superfamily cytokine macrophage inhibitory cytokine-1 is present in high concentrations in the serum of pregnant women
J Clin Endocrinol Metab
(2000) - et al.
Expression of a novel member of the TGF-beta superfamily, growth/differentiation factor-15/macrophage-inhibiting cytokine-1 (GDF-15/MIC-1) in adult rat tissues
Cell Tissue Res
(1999) - et al.
MIC-1 is a novel TGF-beta superfamily cytokine associated with macrophage activation
J Leukoc Biol
(1999) - et al.
Macrophage inhibitory cytokine-1 (MIC-1) in epithelial neoplasia
J Leukoc Biol
(2001) - et al.
PTGF-beta, a type beta transforming growth factor (TGF-beta) superfamily member, is a p53 target gene that inhibits tumor cell growth via TGF-beta signalling pathway
Proc Natl Acad Sci USA
(2000) - et al.
Epitope mapping of the transforming growth factor-beta superfamily protein, macrophage inhibitory cytokine-1 (MIC-1): identification of at least five distinct epitope specificities
Biochemistry
(2001)
Cited by (228)
Circulating total and intact GDF-15 levels are not altered in response to weight loss induced by liraglutide or lorcaserin treatment in humans with obesity
2022, Metabolism: Clinical and ExperimentalAssociation of serum growth differentiation factor-15 levels with the risks of death and vascular events in patients with ischemic stroke: The role of diabetes
2022, Nutrition, Metabolism and Cardiovascular DiseasesGDF-15, a future therapeutic target of glucolipid metabolic disorders and cardiovascular disease
2022, Biomedicine and PharmacotherapyGrowth differentiation factor-15, a novel systemic biomarker of oxidative stress, inflammation, and cellular aging: Potential role in cardiovascular diseases
2021, American Heart Journal Plus: Cardiology Research and PracticeValue of Growth/Differentiation Factor 15 in Diagnosis and the Evaluation of Chemotherapeutic Response in Lung Cancer
2021, Clinical TherapeuticsCitation Excerpt :GDF15 can also significantly increase in the event of trauma, surgery, inflammation, and tumor.17,25 GDF15 has been recognized as a novel molecular marker and its elevation is an independent risk factor for cardiovascular diseases such as coronary atherosclerosis.26 Some studies27,28 have suggested that serum GDF15 level is related to diabetes and obesity.
GDF15 affects venous thrombosis by promoting EndMT through smad2/p-smad2 pathway
2023, Thrombosis Journal