Macrophage Inhibitory Cytokine-1 Gene Research Articles

Enteropathogenic Escherichia coli-induced macrophage inhibitory cytokine 1 mediates cancer cell survival: an in vitro implication of infection-linked tumor dissemination

Mucosally adherent Escherichia coli is frequently observed in intestinal surface of patients with colorectal cancer, but rarely in healthy control. Particularly, enteropathogenic Escherichia coli (EPEC) is known to be closely associated with colorectal carcinogenesis in human. In this study, one consequence of EPEC infection in human intestinal cancer cells was induction of macrophage inhibitory cytokine 1 (MIC-1), which is a multifunctional cytokine with biological activities involved in cancer cell growth, differentiation and migration. The present investigation assessed the involvement of MIC-1 protein in EPEC infection-mediated cancer cell survival. The challenge with EPEC induced cancer cell detachment via cytoskeleton rearrangement, which was positively associated with induced MIC-1 expression. Moreover, MIC-1 also mediated RhoA GTPase-linked survival of the detached cancer cells. Blocking of MIC-1 or RhoA activity increased cellular apoptosis of the detached cancer cells. In terms of signaling pathway, MIC-1 triggered transforming growth factorβ-activated kinase 1 (TAK1), which enhanced expression of RhoA GTPase. We conclude that EPEC enhances MIC-1 gene expression in the human intestinal cancer cells, which can be associated with enhanced tumor cell resistance to anchorage-dependent tumor cell death via enhanced TAK1 and RhoA GTPase.

Macrophage Inhibitory Cytokine-1: A review of its pleiotropic actions in cancer

The macrophage inhibitory cytokine-1 (MIC-1) is a divergent member of the transforming growth factor-β (TGF-β) superfamily that can serve as a potential immune-therapeutic target and/or a prognostic biomarker for the treatment of some cancers. This article reviews the current published data on the molecular and clinical application of MIC-1 in cancer. Literature review was conducted using Medline, PubMed, Embase and Cochrane databases. MIC-1 is the only known secreted p53-regulated cytokine and therefore can serve as a biomarker for p53 activation both in vitro and in vivo. MIC-1 gene can be activated by cyclooxygenase inhibitors and has pro-apoptotic and anti-tumour activities. Although MIC-1 may induce anti-tumour role in the early stages of cancer, it can promote the invasiveness and metastatic behaviour in advanced stages. Greater concentration of MIC-1 was associated with the induction of cancer-related anorexia and weight loss in animals and humans. Of clinical interest, MIC-1 out-performs all available biomarkers including CA19-9 in the differentiation of patients with resectable pancreatic cancer from patients with benign pancreatic disease. MIC-1 gene was over-expressed in colorectal cancer (CRC), and a progressive rise of MIC-1 serum levels was noted in patients with adenomatous polyps and further in patients with CRC. MIC-1 cytokine has the potential characteristics for a new diagnostic biomarker and a target for cancer treatment. Further research however is required to characterise MIC-1 receptors and to revalidate its diagnostic power in larger and better-standardised clinical studies.

Two In-and-out Modulation Strategies for Endoplasmic Reticulum Stress-linked Gene Expression of Pro-apoptotic Macrophage-inhibitory Cytokine 1

Excessive and persistent insults during endoplasmic reticulum (ER) stress lead to apoptotic cell death that is implicated in a range of chronic inflammatory diseases and cancers. Macrophage inhibitory cytokine 1 (MIC-1), a member of the transforming growth factor-β superfamily, is diversely linked to the pathogenesis of cancer. To investigate the precise molecular mechanisms of MIC-1 gene regulation, ER stress and its related signals were studied in human colon cancer cells. Functionally, MIC-1 played pivotal roles in ER stress-linked apoptotic death, which was also influenced by C/EBP homologous protein, a well known apoptotic mediator of ER stress. ER stress enhanced MIC-1 mRNA stability instead of transcriptional activation, and there were two mechanistic translocations critical for mRNA stabilization. First, C/EBP homologous protein triggered protein kinase C-linked cytosolic translocation of the HuR/ELAVL1 (Elav-like RNA-binding protein 1) RNA-binding protein, which bound to and stabilized MIC-1 transcript. As the second critical in-and-out regulation, ER stress-activated ERK1/2 signals contributed to enhanced stabilization of MIC-1 transcript by controlling the extended holding of the nucleated mRNA in the stress granules fusing with the mRNA-decaying processing body. We propose that these two sequential in-and-out modulations can account for stabilized transcription and subsequent translation of pro-apoptotic MIC-1 gene in human cancer cells under ER stress.

Inflammation-associated regulation of the macrophage inhibitory cytokine (MIC-1) gene in prostate cancer

Macrophage inhibitory cytokine-1 (MIC-1), also known as prostate-derived factor (PDF), is a molecule of the TGF-β superfamily and has been associated with the progression of various types of diseases including prostate cancer. Initially identified from activated macrophages, the MIC-1 gene may provide a potential link between inflammation and prostate cancer. In this context, we performed MIC-1 expression analysis using mouse prostate tissues to determine whether there was any correlation with age and inflammation. Reverse transcription PCR analysis on RNA samples isolated from prostate lobes from prostate-specific antigen transgenic mice of varying ages revealed that MIC-1 gene expression is extremely low to non-detectable in the prostate tissues obtained from young mice, while its expression increases in the prostate tissues harvested from elderly mice. Increased MIC-1 gene expression in the mouse prostate was found to be associated with an increased level of infiltrating lymphocytes. To confirm this observation, we showed that inflammation-associated cytokines (IL-1β and TNF-α) significantly upregulate the secretion of the MIC-1 protein in a human prostate cancer cell line (LNCaP cells), while cytokines IL-6 and granulocyte macrophage colony-stimulating factor were less effective. Taken together, these data indicated that inflammation-associated cytokines may play a critical role in the functional regulation of the MIC-1 gene in the early stages of prostate cancer development. More studies are required to understand the biological activity of MIC-1 gene regulation in the development and progression of prostate cancer.

Macrophage Inhibitory Cytokine 1: A New Prognostic Marker in Prostate Cancer

High serum levels of macrophage inhibitory cytokine 1 (MIC-1) are strongly associated with metastatic prostate cancer, suggesting MIC-1 is a biomarker for prostate cancer prognosis. We conducted a prospective cohort study of 1,442 Swedish men with a pathologically verified diagnosis of prostate cancer between 2001 and 2003. Blood was drawn either pretreatment (n = 431) or posttreatment (n = 1,011) and cases were followed for a mean time of 4.9 years (range, 0.1-6.8 years). MIC-1 serum levels independently predicted poor cancer-specific survival with an almost 3-fold higher cancer death rate in patients with serum levels in the highest quartile compared with men with serum levels in the lowest quartile (adjusted hazard ratio, 2.98; 95% confidence interval, 1.82-4.68). Pretreatment MIC-1 levels revealed an even stronger association with disease outcome with an 8-fold higher death rate in the highest compared with the lowest category (adjusted hazard ratio, 7.98; 95% confidence interval, 1.73-36.86). Among patients considered to have localized disease, MIC-1 significantly increased the discriminative capacity between indolent and lethal prostate cancer compared with the established prognostic markers clinical stage, pathologic grade, and prostate-specific antigen level (P = 0.016). A sequence variant in the MIC-1 gene was associated with decreased MIC-1 serum levels (P = 0.002) and decreased prostate cancer mortality (P = 0.003), suggesting a causative role of MIC-1 in prostate cancer prognosis. Serum MIC-1 concentration is a novel biomarker capable of predicting prostate cancer prognosis.

Macrophage inhibitory cytokine-1 (MIC-1) and subsequent urokinase-type plasminogen activator mediate cell death responses by ribotoxic anisomycin in HCT-116 colon cancer cells

Ribosome-inactivating stresses possess a potent regulatory activity against tumor cell progression. In this study, we demonstrated that macrophage inhibitory cytokine-1 (MIC-1) and its associated signals determined the colon cancer cell response to the chemical ribotoxic stress. The ribotoxic stress agent anisomycin-induced MIC-1 gene expression which was involved in the ribotoxin-induced apoptotic pathway. MIC-1 was also a critical inducer of apoptosis-related gene products such as activated urokine-type plasminogen activator (PLAU) and PLAU receptor (uPAR). When MIC-1 or PLAU action was repressed in the tumor cells, the chemical ribotoxic stress triggered a survival-related MAP kinase such as ERK. Mechanistically, gene expression of apoptosis-mediator MIC-1 was enhanced by activating transcription factor 3 (ATF-3) via the p38 MAP kinase signaling pathway. Moreover, both promoter activity and mRNA stability of MIC-1 gene were up-regulated by ribotoxic anisomycin via the p38 MAP kinase signaling pathway. In conclusion, ribotoxic anisomycin-induced MIC-1 expression via p38–ATF3 pathway and subsequent apoptosis while suppressing survival ERK signal in the colon cancer cells. The results of this study provide mechanistic insight into tumor cell decision for death or survival pathways in response to ribosome-disrupting stresses from chemotherapeutics.

Identification of Macrophage Inhibitory Cytokine-1 in Adipose Tissue and Its Secretion as an Adipokine by Human Adipocytes

Macrophage inhibitory cytokine-1 (MIC-1), a divergent member of the TGF-beta superfamily, is involved in the control of multiple cellular processes and mediates cachexia through the inhibition of appetite. Adipose tissue as an endocrine organ secretes proteins (adipokines) that regulate energy homeostasis and other cellular functions. This study investigated whether MIC-1 is expressed in adipose tissue and whether MIC-1 is a secretory product of adipocytes. Mouse and human adipose tissues were collected from different depots. 3T3-L1 preadipocytes and human preadipocytes were induced to differentiate into adipocytes in cell culture. MIC-1 mRNA was detected in the major mouse adipose depots (epididymal, perirenal, sc). In these depots, MIC-1 gene expression was evident in both isolated mature adipocytes and stromal-vascular cells. In 3T3-L1 adipocytes, MIC-1 mRNA was detected before and after differentiation. MIC-1 mRNA and protein secretion were evident in human preadipocytes as well as differentiated adipocytes. MIC-1 production by human adipocytes was stimulated by H(2)O(2) and 15d-prostaglandin J(2). In addition, recombinant MIC-1 increased adiponectin secretion by differentiated human adipocytes. MIC-1 mRNA and protein were also observed in human sc and visceral fat. MIC-1 mRNA levels were positively correlated with adiponectin mRNA. Moreover, MIC-1 mRNA was negatively associated with body mass index and body fat mass in human subjects. We conclude that MIC-1 is expressed in adipose tissue and secreted from adipocytes and is therefore a new adipokine. MIC-1 may have a paracrine role in the modulation of adipose tissue function and body fat mass.

Influence of Inflammation and Aging on Macrophage Inhibitory Cytokine-1 Gene Expression in Rat Ventral Prostate

We have previously reported that the macrophage inhibitory cytokine-1 (MIC-1) gene is downregulated in human symptomatic benign prostatic hyperplasia. The aim of this study was to investigate the histologic changes and MIC-1 gene expression in the prostate of young nonbacterial prostatitis model (Y-NBP) and aging rats. A total of 35 Wistar male rats, 13 weeks old, were castrated and subjected to (a) castration alone for 14 days, (b) Y-NBP-14d (0.25 mg/2 mL/kg beta-estradiol injection for 14 days), or (c) Y-NBP-30d (beta-estradiol injection for 30 days). A total of 5 male rats, 10 months old, were also analyzed. We used 21 male rats, 13 weeks old, who had undergone sham surgery as the controls. The ventral lobes of the prostate were histologically examined with Masson's trichrome staining or immunostaining using an anti-macrophage antibody. The MIC-1 mRNA levels were quantitatively assessed using real-time reverse transcriptase-polymerase chain reaction. The MIC-1 gene mRNA levels in the castration alone, Y-NBP-14d, and Y-NBP-30d rat prostates were greater than those in the control rats (P < .005). In contrast, those of the 10-month-old rats were lower than those of the controls (P = .0093). The mean stroma-to-epithelium ratio in the Y-NBP-30d rats, 10-month-old rats, and 13-week-old controls was 1.28, 0.26, and 0.10, respectively (Y-NBP-30d vs 10-month-old rats, P = .0008; 10-month-old vs 13-week-old rats, P = .001). The number of infiltrating macrophages in the Y-NBP-14d, Y-NBP-30d, and 10-month-old rats was greater than that of the 13-week-old controls (P < .001). Castration causes induction of MIC-1 gene expression. Estradiol treatment has little effect on MIC-1 gene expression but causes a significant increase in the stroma-to-epithelium ratio. The aging rat prostate is more similar to human benign prostatic hyperplasia than is the Y-NBP model in light of MIC-1 gene expression and histologic changes.

재조합 단백질 생산에 이용되는 Pseudomonas fluorescens의 인체 폐포 상피세포의 염증성 인자들의 발현에 미치는 영향

본 연구는 재조합 단백질 생산에 흔히 사용되는 P. fluorescens에 대한 공기 중 노출 시 염증작용이 의심되는 기전을 분석하기 위하여 인체 폐포 상피세포에서의 염증성 인자들 특히 IL-8, COX-2, MIC-1의 발현을 분석하고자 하였다. 균주 P. fluorescens에 대한 인체 폐포 상피세포 A549에서의 세포증식 억제효과를 밝혔고, 상피세포의 염증성 사이토카인으로서 대표적인 인터루킨 8의 발현에 대해서 분석결과. 균주 P. fluorescens및 재조합 균주에 의해 IL-8의 분비가 진핵세포대비 세균세포숫자 의존적으로 생성량이 증대되었다. 또한 점막 상피세포의 염증성 프로스타글란딘 생성에서 핵심적인 역할을 하는 cyclooxygenase-2 (COX-2)에 대해서 P. fluorescens 는 COX-2의 mRNA 발현이 소량 증진되었으나 실제 단백질의 양 및 전사의 변화는 없었다. 일반적으로 단핵구의 염증성 사이토카인 생성에 대하여 억제성 작용을 하는 macrophage inhibitory cytokine 1 (MIC-1)의 발현에 대해서 측정결과 유전자의 발현이 증대되는 효과는 미비하였으나, MIC-1 단백질의 processing에서 propeptide (<TEX>${\sim}28\;kD$</TEX>) 및 mature MIC-1 (<TEX>${\sim}15\;kD$</TEX>)로 분해 되어 MIC-1의 단백질 활성화가 증대되었다. 본 연구에서 보이는 MIC-1은 P. fluorescens에 의한 세포 생존율 억제작용에도 기여할 것으로 예측되며, IL-8에 의한 염증구의 recruitment 대한 억제작용이 예상되나, MIC-1의 활성이 과도하고 지속적으로 나타날 경우 조직의 손상도 가능성도 있다. To investigate the molecular mechanism of the airway inflammation by Pseudomonas fluorescens, effects on the inflammatory mediators such as interleukin-8 (IL-8), cyclooxygenase-2 (COX-2), macophage inhibitory cytokine 1 (MIC-1) were assessed in the human alveolar epithelial cells. Exposure to P. fluorescens and its recombinant bacteria suppressed cellular viability in the A549 epithelial cells and pro-inflammatory cytokine interleukin-8 production. However, pro-inflammatory prostaglandin-producing COX-2 protein was not altered by P. fluorescens though its mRNA was slightly elevated. As the inhibitory cytokine for the pro-inflammatory mediators, MIC-1 expression was monitored in A549 cells. MIC-1 gene induction was not significantly enhanced but the protein processing was changed by exposure to P. fluorescens. Pro-protein form of MIC-1 (<TEX>${\sim}40\;kD$</TEX>) was cleaved into active form mature MIC-1 (<TEX>${\sim}15\;kD$</TEX>) and propeptide (<TEX>${\sim}28\;kD$</TEX>) by the bacteria exposure. MIC-1 activation can contribute to the suppression of cellular viability by P. fluorescens and can retard IL-8-induced monocyte recruitment. However, sustained activation of MIC-1 can mediate the tissue injury by P. fluorescens exposure.

Influence of Inflammation and Aging on Macrophage Inhibitory Cytokine-1 Gene Expression in Rat Ventral Prostate

Influence of Inflammation and Aging on Macrophage Inhibitory Cytokine-1 Gene Expression in Rat Ventral Prostate

Adipocyte culture medium stimulates production of macrophage inhibitory cytokine 1 in MDA-MB-231 cells

Obesity is one of the potential risk factors in causing breast cancer. As a result, adipose tissue surrounding breast ductal cells may play an important role in the breast cancer development or progression. To identify the genes that are regulated by factors secreted from adipocytes in breast cancer cells, MDA-MB-231 cells were treated with the culture medium of adipocytes. Most of induced genes were related to immune function and wound healing, which share a common gene expression signature with cancer progression. In present study macrophage inhibitory cytokine 1 (MIC-1) gene was studied among the induced genes. It was found that both MIC-1 mRNA and protein were dramatically increased by the culture medium of adipocytes. Furthermore, proteinase K-treated adipocyte culture supernatants also induced MIC-1 expression. These findings indicate that proteins are not major MIC-1 inducing factors in adipocyte culture medium. Consequently, we examined the effect of free fatty acids such as palmitate and oleate on MIC-1 induction and found that palmitate markedly induced MIC-1 gene expression, whereas oleate did not. Adipocyte culture medium- and palmitate-induced MIC-1 gene expression was mediated by the activation of p38 MAPK, but not by the activation of JNK, ERK, and NF-κB pathway. In addition, adipocyte-CM-induced MIC-1 also increased invasiveness of MDA-MB-231 cells.

Expression profiling of PC‐3 cell line variants and comparison of MIC‐1 transcript levels in benign and malignant prostate

The mechanisms behind prostate cancer progression are largely unknown, but macrophage inhibitory cytokine 1 (MIC-1) has been suggested to be involved in tumour dissemination in vivo due to its reductive effect on cell adhesion. We used two PC-3 prostate cancer epithelial cell line variants as tools to screen for gene expression differences during prostate cancer progression by cDNA microarray analysis. Selected genes were further analysed by Northern blot analysis using mRNA isolated from prostatic cell lines and tissues. MIC-1 expression was studied by in situ hybridization in archival patient specimens containing benign and malignant prostatic tissue. Gene expression of human collagen type VI, basement membrane heparan sulphate proteoglycan, integrin alpha 1, and fibronectin I were remarkably decreased in suspension-adapted PC-3 (saPC-3) cells, indicating a gene expression profile of reduced cell adhesion. Asparagine synthetase, serine protease 1, stanniocalcin homologue, NAD-dependent methylene tetrahydrate dehydrogenase cyclohydrolase (NMDMC), fortilin, and MIC-1 were overexpressed in saPC-3 cells. In prostate, the MIC-1 gene was mainly expressed in cancer tissue. However, MIC-1 transcripts were detected in benign tissue areas, especially in specimens containing prostate cancer with Gleason sum scores of 5-8. A significant inverse correlation (Spearman's rho correlation coefficient -0.928**) was observed between the ratio of cancerous to benign MIC-1 expression levels and Gleason scores. Differential expression of the MIC-1 gene occurs during prostate cancer progression. The transcript level of the MIC-1 gene in histologically benign tissue seems to approach that in paired cancer tissue concomitant with an increasing Gleason score.

H6D polymorphism in macrophage-inhibitory cytokine-1 gene associated with prostate cancer.

Accumulating epidemiologic and molecular evidence suggest that inflammation is an important component in the etiology of prostate cancer. Macrophage-inhibitory cytokine-1 (MIC-1), a member of the transforming growth factor beta superfamily, is thought to play an important role in inflammation by regulating macrophage activity. We examined whether sequence variants in the MIC-1 gene are associated with the risk of prostate cancer. The study population, a population-based case-control study in Sweden, consisted of 1383 prostate cancer case patients and 780 control subjects. From 94 of the control subjects, we constructed gene-specific haplotypes of MIC-1 and identified four haplotype-tagging single-nucleotide polymorphisms (SNPs): Exon1+25 (V9L), Exon1+142 (S48T), IVS1+1809, and Exon2+2423 (H6D). All study subjects were genotyped for the four SNPs, and conditional logistic regression analysis was used to estimate odds ratios (ORs) with 95% confidence intervals (CIs). A statistically significant difference (P =.006) in genotype frequency was observed for the nonsynonymous change H6D (histidine to aspartic acid at position 6) between prostate cancer patients and control subjects. Carriers of the GC genotype, which results in the H6D change, experienced a lower risk of sporadic prostate cancer (OR = 0.80, 95% CI = 0.66 to 0.97) and of familial prostate cancer (OR = 0.61, 95% CI = 0.42 to 0.89) than the CC genotype carriers. In the study population, the proportion of prostate cancer cases attributable to the CC genotype was 7.2% for sporadic cancer and 19.2% for familial cancer. None of the other SNPs or haplotypes was associated with prostate cancer. This study shows an association between a nonsynonymous change (H6D) in the MIC-1 gene and prostate cancer. This finding supports the hypothesis that genetic variation in the inflammatory process contributes to prostate cancer susceptibility.

ASSOCIATION OF PROSTATIC INFLAMMATION WITH DOWN-REGULATION OF MACROPHAGE INHIBITORY CYTOKINE-1 GENE IN SYMPTOMATIC BENIGN PROSTATIC HYPERPLASIA

Our previous DNA microarray analyses revealed that the macrophage inhibitory cytokine-1 (MIC-1) gene was significantly down-regulated in symptomatic benign prostatic hyperplasia (BPH) samples. We compared the histopathological features of inflammatory changes in prostate adenoma tissues from individuals with symptomatic and asymptomatic (histological only) BPH using MIC-1 mRNA levels. Prostate adenoma tissues were obtained from 25 patients who underwent transurethral prostatectomy to relieve lower urinary tract symptoms due to BPH and 6 patients with bladder cancer who underwent cystoprostatectomy due to bladder cancer. Inflammatory changes in the prostate were examined histopathologically and immunohistochemically, and classified according to the consensus classification system of the Chronic Prostatitis Collaborative Research Network and International Prostatitis Collaborative Network advocated in 2001 with some modification. MIC-1 mRNA was assessed quantitatively by real-time reverse transcriptase-polymerase chain reaction. MIC-1 gene down-regulation was observed in 16 of 25 symptomatic BPH samples (64.0%), whereas MIC-1 mRNA was high in 6 of 6 prostate adenoma samples from patients with bladder cancer (p = 0.0006). MIC-1 gene down-regulation correlated with the grade of glandular/ periglandular inflammatory changes with statistical significance (p = 0.0387). MIC-1 gene down-regulation was found in only 1 of 7 BPH samples with a glandular predominant pattern, whereas it was found in 15 of 24 BPH samples with a mixed type or stromal predominant pattern (p = 0.0373). Gland destruction by inflammatory infiltrates, followed by replacement of the stromal component in symptomatic BPH may be induced by the down-regulation of the MIC-1 gene.

Quantitative analysis of macrophage inhibitory cytokine-1 (MIC-1) gene expression in human prostatic tissues.

Macrophage inhibitory cytokine-1 (MIC-1) gene is a member of transforming growth factor-β superfamily and was reported to be highly overexpressed in human prostate cancer using microarray technology. The aim of this study was to evaluate the quantitative expression of MIC-1 in malignant and benign prostate tissues and to associate expression levels with clinicopathological parameters of prostate cancer. Matched (paired) prostatic tissue samples from the cancerous and noncancerous parts of the same prostates were obtained from 66 patients who underwent radical prostatectomy. Quantitative RT–PCR was performed using SYBR Green I on the Roche LightCycler™ system. Macrophage inhibitory cytokine-1 gene overexpression in cancerous tissues was observed in 88% of cases, compared to noncancerous tissues (P<0.001). The expression level of MIC-1 in cancerous tissues was significantly higher than in noncancerous tissue (P<0.001). Higher expression of MIC-1 gene was significantly associated with higher Gleason score (P=0.004). The expression of the MIC-1 gene in prostate cancer is significantly higher than in noncancerous tissues, especially in more aggressive forms of the disease (Gleason score>5). This is in contrast to prostate-specific antigen that is downregulated in higher-grade tumours. The upregulation of MIC-1 in prostate cancer and in advanced and more aggressive prostatic tumours suggests that MIC-1 protein should be evaluated as a potential diagnostic and prognostic biomarker.

Concentration in plasma of macrophage inhibitory cytokine-1 and risk of cardiovascular events in women: a nested case-control study

Macrophage inhibitory cytokine-1 (MIC-1) is part of the TGF-beta superfamily. Raised concentrations of MIC-1 in serum arise in several disease states, can be detected in normal individuals, and can partly be genetically determined. We aimed to investigate whether MIC-1 has a role in atherothrombosis. We did a prospective, nested, case-control study in 27628 initially healthy women. Of these women, we established baseline concentrations of MIC-1 in 257 who subsequently had myocardial infarction, stroke, or died from a cardiovascular event (cases) and in 257 matched for age and smoking status, who did not report cardiovascular disease during 4-year follow-up (controls). We also assessed polymorphisms in the MIC-1 gene (MIC-1 H and MIC-1 D) in all 514 women. MIC-1 concentrations were higher at baseline in women who subsequently had cardiovascular events than in those who did not (618 vs 538 pg/mL, p=0.0002). Concentrations above the 90th percentile (>856 pg/mL) were associated with a 2.7-fold increase in risk (95% CI 1.6-4.9, p=0.001). This effect was independent of traditional cardiovascular risk factors and at least additive to that of C-reactive protein. There was no significant association between MIC-1 polymorphism and vascular events. MIC-1 could be a novel target for cardiovascular disease prevention.