SJ Levine, P Larivee, C Logun, CW Angus, FP Ognibene and JH Shelhamer
Critical Care Medicine Department, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, Maryland 20892-1662.

Tumor necrosis factor-alpha (TNF-alpha) is a multifunctional, proinflammatory cytokine that is capable of activating a diverse number of target genes within multiple cell types. Little information is known regarding the role of TNF-alpha in the regulation of human airway mucin hypersecretion and MUC-2 gene expression. To assess the effect of TNF- alpha exposure on mucin secretion, human airway organ cultures and primary cultures of human airway epithelial cells were stimulated with 20 ng/ml of recombinant human TNF-alpha and mucin secretion quantitated by an enzyme-linked immunosorbent assay using a specific monoclonal antibody directed against human airway mucin. Significant increases in mucin secretion from human airway organ cultures were initially detected at 1 h, peaked at 8 h, and persisted for 24 h. The TNF-alpha- mediated mucin hypersecretion at 8 h was concentration dependent. Significant increases in mucin secretion from primary cultures of human airway epithelial cells were initially detected at 4 h, peaked at 48 h, and persisted for 72 h after stimulation with 20 ng/ml of recombinant human TNF-alpha. The TNF-alpha-mediated mucin hypersecretion at 48 h from primary cultures of human airway epithelial cells was inhibited by coincubation with soluble 55 kD, type I TNF receptors. Using reverse transcription-polymerase chain reaction and a human pulmonary mucoepidermoid carcinoma cell line (NCI-H292), increases in MUC-2 steady-state mRNA levels were first detectable after 30 min of TNF- alpha stimulation and persisted for 24 h. Cycloheximide did not inhibit TNF-alpha-mediated MUC-2 mRNA expression at 1 h, suggesting that new protein translation was not required.(ABSTRACT TRUNCATED AT 250 WORDS)

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