Involvement of protein kinase Cδ in iron chelator-induced IL-8 production in human intestinal epithelial cells

Abstract: We have shown that the bacterial iron chelator, deferoxamine (DFO), triggers inflammatory signals, including the production of CXC chemokine IL-8, in human intestinal epithelial cells (IECs) by activating ERK1/2 and p38 kinase pathways. In the present study, we show that PKCδ, one of the novel protein kinase C (PKC) isoforms, involves in signal transduction pathways leading to DFO-induced IL-8 production. Pretreatment of human intestinal epithelial HT-29 cells with rottlerin showed remarkable inhibition of DFO-induced IL-8 production. In contrast, other PKC inhibitors such as Gö6976, Gö6983, GF109203X, and staurosporine revealed less or no inhibitory effects on DFO-induced IL-8 production, suggesting a potential role of PKCδ. Accordingly, DFO caused phosphorylation of PKCδ in the Thr505 and Ser643 residues in HT-29 cells. Transfection of dominant-negative PKCδ vector inhibited DFO-induced PKCδ phosphorylation as well as IL-8 promoter activity. In addition, suppression of endogenous PKCδ by siRNA significantly reduced DFO-induced IL-8 production. Collectively, these results suggest that PKCδ plays a pivotal role in signaling pathways leading to iron chelator-induced IL-8 production in human IECs. [Copyright &y& Elsevier]