Regulation of human airway epithelial cell IL-8 expression by MAP kinases

Recent studies indicate that maximal IL-8 protein expression requires activation of NF-κB as well as activation of the MAP kinases ERK, JNK, and p38. However, the precise relationship between NF-κB transactivation and MAP kinase activation remains unclear. We examined the requirements of NF-κB, ERK, JNK, and p38 for TNF-α-induced transcription from the IL-8 promoter in a human bronchial epithelial cell line. Treatment with TNF-α induced activation of all three MAP kinases. Using a combination of chemical and dominant-negative inhibitors, we found that inhibition of NF-κB, ERK, and JNK, but not p38, each decreased TNF-α-induced transcription from the IL-8 promoter. Inhibition of JNK signaling also substantially reduced TNF-α-induced NF-κB transactivation, whereas inhibition of ERK and p38 had no effect. On the other hand, ERK was required and sufficient for TNF-α-induced activation of activator protein (AP)-1 promoter sequences, which together function as a basal level enhancer. JNK activation was also required for AP-1 transactivation. Finally, inhibition of p38 attenuated IL-8 protein abundance, suggesting that p38 regulates IL-8 expression in a posttranscriptional manner. We conclude that, in human airway epithelial cells, MAP kinases may regulate IL-8 promoter activity by NF-κB-dependent (in the case of JNK) and -independent (ERK) processes, as well as by posttranscriptional mechanisms (p38).