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

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.