Macrophages play a key role in both normal and pathological processes involving immune and inf lammatory 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 ␤ (TGF-␤) 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␤, tumor necrosis factor ␣ (TNF-␣), interleukin 2, and macrophage colony-stimulating factor but not interferon ␥, or lipopolysaccharide (LPS). Its expression is also increased by TGF-␤. 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-␣ production, suggesting that MIC-1 acts in macrophages as an autocrine regulatory molecule. Its production in response to secreted proinf lammatory cytokines and TGF-␤ may serve to limit the later phases of macrophage activation.

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.

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