Ubiquitin-mediated destruction of IkB
Active NFkB Inactive NFkB
Figure 1 The activation of the nuclear factor kappa B (NFkB) pathway. NFkB heterodimers (p50/p65) are sequestered in the cytoplasm by IkB inhibitory proteins (IkBa). Stimulation by stress-inducing agents, or exposure to inflammatory cytokines (e.g., TNF-a), mitogens, or a diverse array of bacterial and viral pathogens leads to the activation of signaling cascades converging on the IkB kinase (IKK) complex (highlighted box). Phosphorylation of IkB by activated IKK is regulated by multiple pathways (TAK-1, NIK-1, ASK1, etc.) and is a signal for its ubiquitination and proteasome-dependent degradation. Free NFkB dimers translocate to the nucleus where they bind to kB elements, activating the transcription of a variety of genes involved in the control of cell proliferation, survival as well as inflammatory and immune response (transcriptional control). Other components of the signaling cascade (e.g., p38 pathway) also exert control at the level of translation or mRNA stability (posttranscriptional control).
The interplay with the innate immune system extends further into the family of toll-like receptors (TLRs).6,7 The TLRs are a first-line, pattern-recognition defense, recognizing a diverse array of pathogen-associated molecular patterns, including lipopolysaccharide (LPS), bacterial lipoproteins and lipoteichoic acids, flagellin, double-stranded RNA (dsRNA), single-stranded RNA (ssRNA), and unmethylated CpG DNA of bacteria and viruses. In the gut setting, TLRs have to recognize and respond to both commensal bacteria and pathogenic bacteria in a manner that prevents infection, but does not damage the mucosal tissue. Ligand engagement through TLRs initiates an NFkB-mediated inflammatory response, which is characterized by the recruitment of leukocytes to the site of infection and polarization of Th1 pro-inflammatory responses, through dendritic cell production of IL12. Cell migration and tissue extravasation of cells from the peripheral blood involves a tightly controlled series of events, elicited by chemotactic factors (e.g., IL8, MCP-1, RANTES, MIP-1b). The relevance of this system to IBD, alongside what is being revealed by the function of NOD2, can be illustrated by a number of findings:
• TLR4 is the front-line defense receptor against Gram-negative bacteria and a major LPS transducer. C3H/HeJ mice carry a spontaneous and dominant-negative mutation in TLR4 that results in both LPS unresponsiveness, and a tendency to develop a spontaneous colitis (Table 2).8 Supporting a clinical correlation, an increased association of the TLR4 Asp299Gly polymorphism, which impairs LPS signaling, in patients with UC and CD, compared with normal individuals,9 has been reported. In patients with UC and CD, TLR4 expression also appears to be substantially upregulated.10 That the C5a complement-derived anaphylatoxin is a negative regulator of TLR4 activity and C5a antagonists can attenuate block colitis induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS) gives further support to the important role that TLR4 plays in the control of innate immunity and the host inflammatory response.11,12
• TLR5 recognizes bacterial flagellins, a major target of the Tand B cell response in mouse models of IBD as well as in a subset of patients with CD.13
Table 2 Preclinical transgenic experimental disease models
Spontaneous models C3H/HeJBir
Inflammation is restricted to ileocecal lesions and right-hand side of colon
Multifocal ileitis, enteritis, and cecitis
Cotton-top tamarin Spontaneous model of UC, when kept in captivity
Augmented transgenic models
Enhanced inflammatory response to DSS
CD4 + CD45Rbhi
Inflammation in response to TNP-KLH, exaggerated IL12
signaling and IFN-g production Adoptive transfer model into SCID or Rag2-/ - recipients
Enhanced inflammatory response to DSS, polarized Th2
response Impaired mucosal repair to DSS
Enhanced inflammatory response to DSS
Spontaneous transgenic models
Depletion of regulatory Tcells and activation of Thl cells
Inactivation of regulatory T cell function
In surviving animals, colonic inflammation between 6 and 15 weeks of age
Elevates TNF-a by deletion of the 3' AU-rich regulatory element.
Intestinal efflux pump, mice develop colitis between 12 and 14 weeks of age
Colitis accompanied by marked increase in Thl cytokines
Profound colitis and ileitis by deletion of glutathione peroxidase 1 and 2
ATh2-like colitis develops in mice by about 16 weeks of age
Mice die by 6 weeks of age due to profound CD-like inflammation due to defects in oral tolerance
Inflammation affects stomach, ileum, and the entire colon
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