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MIC-1, a divergent member of the TGF-b superfamily is induced by a range of pro-inflammatory cytokines and oxLDL and is highly expressed in macrophages in atherosclerotic and tumour lesions.MIC-1, a major p53 target gene, is largely described to have anti-tumorigenic activity and more recently high MIC-1 serum levels in late stage cancer were shown to be the major cause of cancer associated weight loss.MIC-1 serum levels independently predict both atherosclerotic events and severity of rheumatoid arthritis, suggesting serum levels are important in modifying disease expression.Controlling serum levels is the ratio of latent unprocessed MIC-1 stromal stores to soluble mature MIC-1 generated by the cell.Here we investigate MIC-1 secretion from U937 monocytoid cells and identify novel mechanisms designed to ensure secretion of unprocessed cytokine and creation of latent stromal stores.We find endogenous MIC-1 is secreted as both processed and unprocessed forms.Pulse chase analysis of MIC-1 secretion reveals unprocessed MIC-1 precursor is rapidly secreted, whilst mature MIC-1 generated within the cell by intracellular processing, is secreted much slower, possibly via an alternate secretory route.The COOH-T47 amino acids of the propeptide are responsible for rapid secretion of MIC-1 precursor and this effect occurs in the trans-Golgi network (TGN)/post TGN compartment.Thus, variations in MIC-1 intracellular processing, regulating the presence or absence of propeptide, is a powerful mechanism modulating rate of MIC-1 secretion and proMIC-1 stromal storage, with major impact on circulating levels of mature MIC-1.