NF-kappa B is a central regulator of the intestinal epithelial cell innateimmune response induced by infection with enteroinvasive bacterial

Human intestinal epithelial cells up-regulate the expression of an inflamma tory. gene program in response to infection with a spectrum of different st rains of enteroinvasive bacteria. The conserved nature of this program sugg ested that diverse signals, which are activated by enteroinvasive bacteria, can be integrated into a common signaling pathway that activates a set of proinflammatory genes in infected host cells. Human intestinal epithelial c ell lines, HT-29, Caco-2, and T84, were infected with invasive bacteria tha t use different strategies to induce their uptake and have different intrac ellular localizations (i.e., Salmonella dublin, enteroinvasive Escherichia coil, or Yersinia enterocolitica), Infection with each of these bacteria re sulted in the activation of TNF receptor associated factors, two recently d escribed serine kinases, I kappa B kinase (IKK) alpha and IKK beta, and inc reased NF-kappa B DNA binding activity. This was paralleled by partial degr adation of I kappa B alpha and I kappa B epsilon in bacteria-infected Caco- 2 cells, Mutant proteins that act as superrepressors of IKK beta and I kapp a B alpha inhibited the up-regulated transcription and expression of downst ream targets genes of NF-B kappa that are key components of the epithelial inflammatory gene program (i.e., IL-8, growth-related oncogene-alpha, monoc yte chemoattractant protein-1, TNF-alpha, cyclooxygenase-2, nitric oxide sy nthase-2, ICAM-1) activated by those enteroinvasive bacteria. These studies position NF-kappa B as a central regulator of the epithelial cell innate i mmune response to infection with enteroinvasive bacteria.