Monocyte/macrophages evoke epithelial dysfunction: indirect role of tumor necrosis factor-alpha

We examined theability of monocytes (M) activated by bacterial products to alterepithelial physiology. Confluent monolayers of the T84 colonicepithelial cell line were grown on filter supports and then coculturedin the presence of human M with or without the activating agentsbacterial lipopolysaccharide and the bacterial tripeptideformyl-methionyl-leucyl-phenylalanine. After 24 or 48 h, monolayerswere mounted in Ussing chambers where parameters of epithelial functionwere measured. Exposure to activated M resulted in a significantincrease (P < 0.05) in baselineshort-circuit current (250% after 48 h) that was associated withenhanced secretion of Cl.In addition, epithelial permeability was significantly increased asshown by reduced transepithelial resistance and increased flux of⁵¹Cr-EDTA. Activated M producedsubstantial amounts (~3 ng/ml at 48 h) of tumor necrosis factor-(TNF-). TNF- was identified as a key mediator acting via anautocrine mechanism to induce epithelial pathophysiology. Our data showthat M, when activated by common bacterial components, are potenteffector cells capable of initiating significant changes in thetransport and barrier properties of a model epithelium.