Induction of cytokine synthesis by flagella from gram-negative bacteria may be dependent on the activation or differentiation state of human monocytes

We have previously demonstrated that salmonellae, but not Escherichia coli or Yersinia enterocolitica, stimulates tumor necrosis factor alpha (TNF alpha) production in the human promonocytic cell line U38. Subsequent analysis revealed that the TNF alpha-inducing activity of salmonellae was associated with flagellin, a major component of flagella from gram-negative bacteria. In the present study, we have explored the basis for the apparent specificity of action of Salmonella flagella on TNF alpha expression in U38 cells and have extended this analysis to normal human peripheral blood mononuclear cells (PBMC). Flagella from the enteropathogenic E. coli strain E2348/69, Y. enterocolitica JB580, and Pseudomonas aeruginosa PAO1, which did not induce significant levels of TNF alpha production in U38 cells, were as potent as Salmonella flagella in terms of TNF alpha and interleukin 1 beta activation in PBMC. However, TNF alpha production in U38 cells was greatly enhanced when these cells were stimulated with flagella from E. coli, Y. enterocolitica, and P. aeruginosa in the presence of a costimulant, phorbol 13-myristate acetate. These findings are consistent with the hypothesis that the activation or differentiation state of a monocyte may have a substantial effect on the cell's responsiveness to flagellum stimulation of cytokine synthesis. Furthermore, these results indicate that cytokine induction in monocytes may be a general property of flagella from gram-negative bacteria.