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Infection and Immunity, March 2004, p. 1487-1495, Vol. 72, No. 3
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.3.1487-1495.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Nod1 Is an Essential Signal Transducer in Intestinal Epithelial Cells Infected with Bacteria That Avoid Recognition by Toll-Like Receptors

Jae Gyu Kim,{dagger} Sung Joong Lee,{ddagger} and Martin F. Kagnoff*

Laboratory of Mucosal Immunology, University of California at San Diego, La Jolla, California 92093-0623

Received 9 September 2003/ Accepted 10 December 2003

The transcription factor NF-{kappa}B 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-{kappa}B. The aim of these studies was to assess the functional importance of Nod1 in activating NF-{kappa}B and NF-{kappa}B 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-{kappa}B in response to bacterial flagellin or IL-1 stimulation. Stable expression of dominant negative (DN) Nod1 in colon epithelial cells prevented I{kappa}B kinase and NF-{kappa}B activation in response to infection with enteroinvasive Escherichia coli. In contrast, DN Nod1 did not eliminate IL-1 or flagellin-stimulated NF-{kappa}B activation. Inhibition of NF-{kappa}B was accompanied by inhibition of NF-{kappa}B 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-{kappa}B 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.

* Corresponding author. Mailing address: Laboratory of Mucosal Immunology, Departments of Medicine and Pediatrics, University of California at San Diego, Mail Code 0623D, La Jolla, CA 92093-0623. Phone: (858) 534-4622. Fax: (858) 534-5691. E-mail: mkagnoff{at}ucsd.edu.

Editor: F. C. Fang

{dagger} Present address: Department of Medicine, Chung-Ang University College of Medicine, Jung-Ku, Seoul, 100-272, Korea.

{ddagger} Present address: Department of Structure and Functional Biology, College of Dentistry, Seoul National University, Chongno-Ku, Seoul, 110-749, Korea.

Infection and Immunity, March 2004, p. 1487-1495, Vol. 72, No. 3
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.3.1487-1495.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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