Growth differentiation Factor-15/Macrophage inhibitory cytokine-1 induction through P53- and Tnf-independent mechanisms in liver, kidney, and lung injury

Abstract

Macrophage inhibitory cytokine-1 (MIC-1) is a divergent TGF-β family member overexpressed in numerous malignancies. Expression of MIC-1 correlates with disease stage in pancreatic and colon cancer and has been proposed as a potential diagnostic and prognostic biomarker. We have previously shown that the murine ortholog of MIC-1, Growth/Differentiation Factor-15 (GDF-15), is highly expressed in response to various acute liver injuries including those associated with subsequent carcinogenesis. Here we show that MIC-1 is overexpressed in chronic human liver disease, and furthermore, that GDF-15 is expressed in liver, kidney, and lung in various models of acute organ injury, including toxic/genotoxic, ischemic, surgical, and hyperoxic. We also show that Gdf15 is an immediate-early gene. GDF-15 expression after injury may be induced by the inflammatory response, since administration of TNF and, to a lesser extent IL-6, induced expression of Gdf15. Injury-induced Gdf15 expression was not reduced in mice deficient for both TNF receptor subtypes, however, suggesting that cytokine signaling is not required for GDF-15 expression. As well, although the stress sensor p53 is widely recognized to induce MIC-1 expression, injury-induced Gdf15 expression was unchanged in p53 null mice. Our results demonstrate that GDF-15 expression following injury is regulated by both paracrine (cytokine) and autocrine (p53) mechanisms, and in more tissues than previously recognized. Taken together with its described activities, these data suggest that MIC-1/GDF-15 production may regulate inflammation, cell proliferation, apoptosis, and perhaps migration in injured tissues, and moreover, may influence carcinogenesis and cancer progression in settings of genotoxic injury.