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-kappaB as well as activation of the MAP kinases ERK, JNK, and p38. However, the precise relationship between NF-kappaB transactivation and MAP kinase activation remains unclear. We examined the requirements of NF-kappaB, ERK, JNK, and p38 for TNF-alpha-induced transcription from the IL-8 promoter in a human bronchial epithelial cell line. Treatment with TNF-alpha induced activation of all three MAP kinases. Using a combination of chemical and dominant-negative inhibitors, we found that inhibition of NF-kappaB, ERK, and JNK, but not p38, each decreased TNF-alpha-induced transcription from the IL-8 promoter. Inhibition of JNK signaling also substantially reduced TNF-alpha-induced NF-kappaB transactivation, whereas inhibition of ERK and p38 had no effect. On the other hand, ERK was required and sufficient for TNF-alpha-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-kappaB-dependent (in the case of JNK) and -independent (ERK) processes, as well as by posttranscriptional mechanisms (p38).
Li
Jing
J
Kartha
Sreedharan
S
Iasvovskaia
Svetlana
S
Tan
Alan
A
Bhat
Rajesh K
RK
Manaligod
Joel M
JM
Page
Kristen
K
Brasier
Allan R
AR
Hershenson
Marc B
MB
D000470:Alkaloids / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D002460:Cell Line; D015870:Gene Expression / Q000276:immunology; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics* / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology*; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000276:immunology; D020545:Respiratory Mucosa / Q000166:cytology* / Q000201:enzymology* / Q000276:immunology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
D000470:Alkaloids; D000970:Antineoplastic Agents; D016209:Interleukin-8; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; C079965:neojiangyouaconitine; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases