Open AccessNod1 Is an Essential Signal Transducer in Intestinal Epithelial Cells Infected with Bacteria That Avoid Recognition by Toll-Like Receptors
Author(s) -
Jae Gyu Kim,
Sung Joong Lee,
Martin F. Kagnoff
Publication year - 2004
Publication title -
infection and immunity
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.508
H-Index - 220
eISSN - 1070-6313
pISSN - 0019-9567
DOI - 10.1128/iai.72.3.1487-1495.2004
Subject(s) - nod1 , biology , tlr5 , flagellin , intestinal epithelium , nod2 , tlr4 , innate immune system , microbiology and biotechnology , signal transduction , proinflammatory cytokine , toll like receptor , lipopolysaccharide , pattern recognition receptor , tlr2 , intestinal mucosa , receptor , nf κb , immunology , epithelium , inflammation , immune system , medicine , biochemistry , genetics
The transcription factor NF-kappaB in human intestinal epithelial cells plays a central role in regulating genes that govern the onset of mucosal inflammatory responses following intestinal microbial infection. Nod1 is a cytosolic pattern recognition receptor in mammalian cells that senses components of microbial peptidoglycans and signals the activation of NF-kappaB. The aim of these studies was to assess the functional importance of Nod1 in activating NF-kappaB and NF-kappaB proinflammatory target genes in human intestinal epithelium. Human colon epithelial cells that constitutively express Nod1 were used as a model intestinal epithelium. These cells do not signal through Toll-like receptor 4 (TLR4) or respond to bacterial lipopolysaccharide, but they express functional TLR5 and interleukin 1 (IL-1) receptors that signal the activation of NF-kappaB in response to bacterial flagellin or IL-1 stimulation. Stable expression of dominant negative (DN) Nod1 in colon epithelial cells prevented IkappaB kinase and NF-kappaB activation in response to infection with enteroinvasive Escherichia coli. In contrast, DN Nod1 did not eliminate IL-1 or flagellin-stimulated NF-kappaB activation. Inhibition of NF-kappaB was accompanied by inhibition of NF-kappaB target genes that provide signals for the mucosal influx of neutrophils during intestinal infection. We conclude that signaling through Nod1 is required for activating NF-kappaB in human intestinal epithelial cells infected with gram-negative enteric bacteria that can bypass TLR activation. Signaling through Nod1 provides the intestinal epithelium with a backup mechanism for rapidly activating innate immunity during infection with a group of highly invasive pathogenic gram-negative bacteria.