The TGF-b superfamily cytokine MIC-1/GDF15 circulates in all humans and when overproduced in cancer leads to anorexia/cachexia, by direct action on brain feeding centres. In these studies we have ...examined the role of physiologically relevant levels of MIC-1/GDF15 in the regulation of appetite, body weight and basal metabolic rate. MIC-1/GDF15 gene knockout mice (MIC-1(-/-)) weighed more and had increased adiposity, which was associated with increased spontaneous food intake. Female MIC-1(-/-) mice exhibited some additional alterations in reduced basal energy expenditure and physical activity, possibly owing to the associated decrease in total lean mass. Further, infusion of human recombinant MIC-1/GDF15 sufficient to raise serum levels in MIC-1(-/-) mice to within the normal human range reduced body weight and food intake. Taken together, our findings suggest that MIC-1/GDF15 is involved in the physiological regulation of appetite and energy storage.
Food intake and body weight are controlled by a variety of central and peripheral factors, but the exact mechanisms behind these processes are still not fully understood. Here we show that that ...macrophage inhibitory cytokine-1 (MIC-1/GDF15), known to have anorexigenic effects particularly in cancer, provides protection against the development of obesity. Both under a normal chow diet and an obesogenic diet, the transgenic overexpression of MIC-1/GDF15 in mice leads to decreased body weight and fat mass. This lean phenotype was associated with decreased spontaneous but not fasting-induced food intake, on a background of unaltered energy expenditure and reduced physical activity. Importantly, the overexpression of MIC-1/GDF15 improved glucose tolerance, both under normal and high fat-fed conditions. Altogether, this work shows that the molecule MIC-1/GDF15 might be beneficial for the treatment of obesity as well as perturbations in glucose homeostasis.
Macrophage inhibitory cytokine-1 (MIC-1), a transforming growth factor-beta superfamily cytokine, is involved in tumor pathogenesis, and its measurement can be used as a clinical tool for the ...diagnosis and management of a wide range of cancers. Although generally considered to be part of the cell's antitumorigenic repertoire, MIC-1 secretion, processing, and latent storage suggest a complex, dynamic variability in MIC-1 bioavailability in the tumor microenvironment, potentially modulating tumor progression and invasiveness.
In humans and most mammals, differentiation of the embryonic gonad into ovaries or testes is controlled by the Y-linked gene SRY. Here we show a role for the Gadd45g protein in this primary sex ...differentiation. We characterized mice deficient in Gadd45a, Gadd45b and Gadd45g, as well as double-knockout mice for Gadd45ab, Gadd45ag and Gadd45bg, and found a specific role for Gadd45g in male fertility and testis development. Gadd45g-deficient XY mice on a mixed 129/C57BL/6 background showed varying degrees of disorders of sexual development (DSD), ranging from male infertility to an intersex phenotype or complete gonadal dysgenesis (CGD). On a pure C57BL/6 (B6) background, all Gadd45g(-/-) XY mice were born as completely sex-reversed XY-females, whereas lack of Gadd45a and/or Gadd45b did not affect primary sex determination or testis development. Gadd45g expression was similar in female and male embryonic gonads, and peaked around the time of sex differentiation at 11.5 days post-coitum (dpc). The molecular cause of the sex reversal was the failure of Gadd45g(-/-) XY gonads to achieve the SRY expression threshold necessary for testes differentiation, resulting in ovary and Müllerian duct development. These results identify Gadd45g as a candidate gene for male infertility and 46,XY sex reversal in humans.
The extracellular matrix (ECM) is a reservoir of cellular binding proteins and growth factors that are critical for normal cell behavior, and aberrations in the ECM invariably accompany malignancies ...such as prostate cancer. Carcinomas commonly overexpress macrophage inhibitory cytokine 1 (MIC-1), a proapoptotic and antitumorigenic transforming growth factor-beta superfamily cytokine. Here we show that MIC-1 is often secreted in an unprocessed propeptide containing form. It is variably processed intracellularly, with unprocessed forms being secreted from several tumor lines, including prostate carcinoma lines, PC-3 and LNCaP. Once secreted, only unprocessed proMIC-1 binds ECM, demonstrating for the first time the occurrence of extracellular stores of MIC-1. The propeptide mediates this association via its COOH-terminal 89 amino acids. Xenograft models bearing tumors secreting various engineered forms of MIC-1 show that the propeptide regulates the balance between ECM stores and circulating serum levels of mature MIC-1 in vivo. The absence of propeptide results in approximately 20-fold increase in serum MIC-1 levels. The significance of stromal MIC-1 stores was evaluated in prostate cancer tissue cores, which show major variation in stromal levels of MIC-1. Stromal MIC-1 levels are linked to prostate cancer outcome following radical prostatectomy, with decreasing stromal levels providing an important independent predictor of disease relapse. In low-grade localized prostate cancer (Gleason sum score < or = 6), the level of MIC-1 stromal stores was the best predictor of future relapse when compared with all other clinicopathologic variables. The secretion and ECM association of unprocessed proMIC-1 is likely to play a central role in modulating local bioavailability of MIC-1 which can affect patient outcome in prostate cancer and other epithelial tumors.
Anorexia and weight loss are part of the wasting syndrome of late-stage cancer, are a major cause of morbidity and mortality in cancer, and are thought to be cytokine mediated. Macrophage inhibitory ...cytokine-1 (MIC-1) is produced by many cancers. Examination of sera from individuals with advanced prostate cancer showed a direct relationship between MIC-1 abundance and cancer-associated weight loss. In mice with xenografted prostate tumors, elevated MIC-1 levels were also associated with marked weight, fat and lean tissue loss that was mediated by decreased food intake and was reversed by administration of antibody to MIC-1. Additionally, normal mice given systemic MIC-1 and transgenic mice overexpressing MIC-1 showed hypophagia and reduced body weight. MIC-1 mediates its effects by central mechanisms that implicate the hypothalamic transforming growth factor-beta receptor II, extracellular signal-regulated kinases 1 and 2, signal transducer and activator of transcription-3, neuropeptide Y and pro-opiomelanocortin. Thus, MIC-1 is a newly defined central regulator of appetite and a potential target for the treatment of both cancer anorexia and weight loss, as well as of obesity.
Macrophage inhibitory cytokine-1 (MIC-1/GDF15) is associated with cardiovascular disease, inflammation, body weight regulation and cancer. Its serum levels facilitate the diagnosis and prognosis of ...cancer and vascular disease. Furthermore, its serum levels are a powerful predictor of all-cause mortality, suggesting a fundamental role in biological processes associated with ageing. In cancer, the data available suggest that MIC-1/GDF15 is antitumorigenic, but this may not always be the case as disease progresses. Cancer promoting effects of MIC-1/GDF15 may be due, in part, to effects on antitumour immunity. This is suggested by the anti-inflammatory and immunosuppressive properties of MIC-1/GDF15 in animal models of atherosclerosis and rheumatoid arthritis. Furthermore, in late-stage cancer, large amounts of MIC-1/GDF15 in the circulation suppress appetite and mediate cancer anorexia/cachexia, which can be reversed by monoclonal antibodies in animals. Available data suggest MIC-1/GDF15 may be an important molecule mediating the interplay between cancer, obesity and chronic inflammation.
Immunotherapy of cancer by vaccination is hampered by tumour-mediated immune suppression, to which pro-inflammatory cytokines such as interleukin-1 (IL-1) and IL-6 contribute. In mouse models, ...IL-1-receptor antagonist (IL-1 Ra) diminished inflammation and tumour growth when administered during or shortly after tumour inoculation.
The capacity of IL-1 Ra anakinra to reduce IL-1-induced production of IL-6 in order to improve the efficacy of a subsequent booster vaccination with survivin-derived peptides and soluble β-glucan as adjuvant was tested in colon-26 adenocarcinoma-bearing Balb/c-mice.
Bolus administration of anakinra into non-immunized mice with macroscopic tumour significantly lowered serum levels of IL-6 without inhibiting tumour growth. When administered to pre-immunized mice bearing a palpable tumour, IL-1 Ra enhanced growth inhibition of a subsequent booster vaccination, although serum-IL-6 was not reduced and the number of IFN-γ-producing splenic CD8(+) T-cells was not increased.
Anakinra contributes to growth-inhibition of small tumours, presumably by blocking IL-1 as tumour growth-promoting factor rather than by facilitating an enhanced CTL response.
Abstract Aim MIC-1/GDF15 is a member of the TGF-b superfamily, which is thought to have pleiotropic roles in stress responses, inflammation, tissue injury and repair, energy homeostasis, and ...malignancy. MIC-1/GDF15 was recently identified as a new biomarker for the development of cardiovascular events and the outcome of atherosclerotic disease therapy. The aim of our study was to determine if MIC-1 also directly exerts pro- or antiatherogenic properties during the development of atherosclerosis. Methods and results We investigated the effect of transgenic overexpression of MIC-1 in macrophages in the ApoE−/− mouse model of atherosclerosis. After 6 months of high-fat diet, MIC-1/GDF15 transgenic ApoE−/− mice had smaller atherosclerotic lesions; however, no differences in lesion composition, pro- or anti-inflammatory cytokine production, or serum levels of lipids or cytokines were detected. Conclusions Our results suggest that MIC-1 has an overall protective effect on the disease process, but further studies will be required to define its mechanism of action.
Human NK cell lines providing an unlimited source of effector cells might be suitable for use in adoptive immunotherapy. This study determined the cytolytic activity of the human NK-like cell line YT ...against myeloma cell lines and primary myeloma cells.
Lysis of the myeloma cell lines MM1S and U266 and of primary human myeloma cells by YT was measured using a flow-cytometric cytotoxicity assay. Furthermore, it was investigated whether the cytotoxicity correlates with the expression of CD86 on myeloma cells and the effect of different doses of IL-2 on cytolysis was tested.
YT showed killing of myeloma cell lines and primary myeloma cells. The extent of cytolysis correlated with the expression of CD86 on myeloma cells and was not augmented by preincubation of YT with high dose of IL-2.
The human NK-like cell line YT could be useful in immunotherapy of patients with CD86(+) multiple myeloma.
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