Iron chelator differentially activates macrophage inflammatory protein-3α/CCL20 in immortalized and malignant human oral keratinocytes

Macrophage inflammatory protein-3α (MIP-3α or CCL20) is an intriguing molecule in cancer immunotherapy, but MIP-3α expression and signalling are not well understood in oral cancer cells. We investigated CCL20 expression and signal transduction by treating immortalized human oral keratinocyte (IHOK) and oral cancer (HN4) cells with deferoxamine (DFO) and examined the mRNA expression of CCL20 using RT-PCR and ELISA. IHOK and HN4 cells treated with DFO showed increased mRNA and protein expression of CCL20, and the upregulation of DFO-induced CCL20 expression was higher in IHOK cells than in HN4 cells. Selective inhibitors of p38 and ERK1/2 abolished DFO-induced CCL20 expression in both IHOK and HN12 cells, and p38 and ERK1/2 inhibitors prevented DFO-induced degradation of I-κB and NF-κB activation. Activation of c-fos and c-jun also occurred following DFO treatment in IHOK and HN4 cells. Collectively, these results suggest that DFO-induced MIP-3α, which is involved in the MAP kinase, c-fos, c-jun, and NF-κB pathways, may be an important mediator of the antitumour immune response in oral keratinocytes and warrants consideration as a target molecule for oral cancer treatment.