Macrophage colony stimulating factor expression in human cardiac cells is upregulated by tumor necrosis factor-α via an NF-κB dependent mechanism

Abstract

Introduction: Macrophage colony stimulating factor (M-CSF) is a key factor for monocyte and macrophage survival and proliferation. M-CSF has been implicated in cardiac healing and repair after myocardial infarction. Methods and results: We show by immunohistochemistry and Western blotting analysis that M-CSF protein is present in human heart tissue. Cultured human adult cardiac myocytes (HACM) and human adult cardiac fibroblasts (HACF) isolated from human myocardial tissue constitutively express M-CSF. When HACM and HACF were treated with tumor necrosis factor-α (TNF-α) M-CSF protein production and M-CSF mRNA expression, determined by ELISA or by using RT-PCR, respectively, was significantly increased. To determine a possible role of nuclear factor κB (NF-κB) and activating protein 1 (AP-1) in M-CSF regulation, blockers to both pathways and an adenovirus overexpressing a dominant negative (dn) form of IκB kinase 2 (IKK2) were used. Only the NF-κB blocker dimethylfumarate and the dn IKK2, but not januskinase inhibitor-1 (JNK-I), were able to block the TNF-α-induced increase in M-CSF production in these cells, suggesting that the induction of M-CSF through TNF-α is mainly dependent on the activation of the NF-κB pathway. The monocyte activation marker CD11b was significantly increased after incubating U937 cells with conditioned medium from HACM or HACF as determined by FACS analysis. Conclusions: Our in vitro data taken together with our immunohistochemistry data suggest that human cardiac cells constitutively express M-CSF. This expression of M-CSF in the human heart and its upregulation by TNF-α might contribute to monocyte and macrophage survival and differentiation. © 2007 International Society on Thrombosis and Haemostasis.