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

1 Department of Pediatrics, University of Chicago, Chicago, Illinois 60637; and 2 Department of Medicine, University of Texas Medical Branch, Galveston, Texas 77555-1060 Recent studies indicate that maximal IL-8 protein expression requires activation of NF- B as well as activation of the MAP kinases ERK, JNK, and p38. However, the precise relationship between NF- B transactivation and MAP kinase activation remains unclear. We examined the requirements of NF- B, ERK, JNK, and p38 for TNF- -induced transcription from the IL-8 promoter in a human bronchial epithelial cell line. Treatment with TNF- induced activation of all three MAP kinases. Using a combination of chemical and dominant-negative inhibitors, we found that inhibition of NF- B, ERK, and JNK, but not p38, each decreased TNF- -induced transcription from the IL-8 promoter. Inhibition of JNK signaling also substantially reduced TNF- -induced NF- B transactivation, whereas inhibition of ERK and p38 had no effect. On the other hand, ERK was required and sufficient for TNF- -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- B-dependent (in the case of JNK) and -independent (ERK) processes, as well as by posttranscriptional mechanisms (p38). cytokines; inflammation; signal transduction; transcription factors; interleukin 8; mitogen-activated protein * J. Li and S. Kartha contributed equally to this work.