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TNF- induces MUC1 gene transcription in lung epithelial cells: its signaling pathway and biological implication

¹Lovelace Respiratory Research Institute, Albuquerque, New Mexico; ²Kumamoto University, Kumamoto, Japan; ³University of Maryland, Baltimore; and ⁴Johns Hopkins University, Baltimore, Maryland

Submitted 22 December 2006 ; accepted in final form 6 June 2007

The current study was conducted to elucidate the mechanism through which TNF- stimulates expression of MUC1, a membrane-tethered mucin. A549 human lung alveolar cells treated with TNF- exhibited significantly higher MUC1 protein levels in detergent lysates compared with cells treated with vehicle alone. Increased MUC1 protein levels were correlated with significantly higher levels of MUC1 mRNA in TNF--treated cells compared with controls. However, TNF- did not alter MUC1 transcript stability, implying increased de novo transcription induced by the cytokine. TNF- increased MUC1 gene promoter activity in A549 cells transfected with a promoter-luciferase reporter plasmid. Both U0126, an inhibitor of MEK1/2, and dominant negative ERK1 prevented TNF--induced MUC1 promoter activation, and anti-TNFR1 antibody blocked TNF--stimulated ERK1/2 activation. MUC1 promoter activation by TNF- also was blocked by mithramycin A, an inhibitor of Sp1, as well as either deletion or mutation of a putative Sp1 binding site in the MUC1 promoter located between nucleotides –99 and –90. TNF--stimulated binding of Sp1 to the MUC1 promoter in intact cells was demonstrated by chromatin immunoprecipitation assay. We conclude that TNF- induces MUC1 gene transcription through a TNFR1 MEK1/2 ERK1 Sp1 pathway.

tumor necrosis factor-; Sp1; mitogen-activated protein kinase

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				K. Ueno, T. Koga, K. Kato, D. T. Golenbock, S. J. Gendler, H. Kai, and K. C. Kim MUC1 Mucin Is a Negative Regulator of Toll-Like Receptor Signaling Am. J. Respir. Cell Mol. Biol., March 1, 2008; 38(3): 263 - 268. [Abstract] [Full Text] [PDF]