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

The innate immune system recognizes "non-self" by employing a set of germline-encoded receptors called Toll-like receptors (TLRs), originally characterized in Drosophila. TLRs are involved in the recognition of various microbial-derived molecules, including lipopolysaccharide (LPS), lipoteichoic acid (LTA), and peptidoglycan (PGN), as well as unmethylated bacterial DNA. The TLR-mediated intracellular signaling pathways converge to activate nuclear factor-kappa B (NF-kappaB) and c-Jun N-terminal kinases (JNKs), which induce the transcription of a series of cytokine/chemokine genes that are involved in the initiation or regulation of the inflammatory response. It is now known that, like other peripheral organs, the central nervous system (CNS) is also under constitutive immune surveillance by CNS-resident glial cells (microglia and astrocytes) and CNS-infiltrating immune cells. The recent progress in our understanding of TLR functions in the innate immune response sheds new light on how inflammatory immune responses are initiated within the CNS. In this review, we discuss recent studies on TLRs and their ligands, signal transduction pathways activated by TLRs, and the mechanisms through which these various activation events occur. Finally, we discuss how TLRs might play similar important roles in CNS inflammation.