Gnotobiotic IL-10−/−;NF-κBEGFP Mice Reveal the Critical Role of TLR/NF-κB Signaling in Commensal Bacteria-Induced Colitis

Karrasch, Thomas; Kim, Sang Woo; Mühlbauer, Marcus; Magness, Scott T.; Jobin, Christian

doi:10.4049/jimmunol.178.10.6522

Cited by 109 publications

(100 citation statements)

References 67 publications

(56 reference statements)

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“…We found that DALDA significantly reduced colonic Tnf and Il6 mRNA expression ( Figure 1F). Because these cytokines are induced in part through immune-derived NF-B signaling during experimental colitis, 34 we next explored the effect of daily s.c. injections of DALDA on NF-B activity with the use of fresh-fixed tissue sections obtained from NF-B EGFP reporter mice and confocal microscopy imaging. As previously reported, EGFP expression in the lamina propria increased in DSS-exposed NF-B EGFP reporter mice.…”

Section: Dalda Ameliorates Dss-induced Intestinal Injurymentioning

confidence: 99%

Mu Opioid Signaling Protects Against Acute Murine Intestinal Injury in a Manner Involving Stat3 Signaling

Goldsmith

Uronis

Jobin

2011

The American Journal of Pathology

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Opiates have long been used as analgesics to relieve pain associated with various medical conditions. Here, we evaluated the effect and mechanism of mu opioid signaling on the intestinal wound healing response and assessed downstream pathways known to be protective against intestinal injury. Mice (C57BL/6) were exposed to 3% dextran sodium sulfate (DSS) for 7 days or 4% DSS for 5 days followed by 7 days of water. The mu opioid receptor (MOR)-specific agonist [D-Arg2,Lys4]dermorphin-(1,4)-amide (DALDA) and the antagonist cyprodime were injected s.c. daily for in vivo studies or used for in vitro analysis. We found that MOR activation attenuated DSS-induced histologic and gross intestinal injury and weight loss; diminished Ifng, Tnf, and Il6 mRNA expression; and promoted intestinal healing during recovery. DALDA also enhanced colonocyte proliferation (Ki-67 staining) by 350%. MOR activation increased Stat3 phosphorylation in both DALDA-treated mice and the CMT-93 cell line. Importantly, DALDAinduced colonocyte migration was completely ablated by shStat3 knockdown. Together, this work shows that MOR activation protects against and enhances recovery from DSS-induced intestinal injury. This is associated with an increase in Stat3 activation. Furthermore, Stat3 is required for DALDA-induced colonocyte migration. Consequently, manipulation of MOR signaling may represent a novel means to promote mucosal healing and to maintain intestinal homeostasis after intestinal injury.

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Section: Dalda Ameliorates Dss-induced Intestinal Injurymentioning

confidence: 99%

Mu Opioid Signaling Protects Against Acute Murine Intestinal Injury in a Manner Involving Stat3 Signaling

Goldsmith

Uronis

Jobin

2011

The American Journal of Pathology

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“…, and collagen type 1a YFP mice were generated as previously described (27)(28)(29)(30)(31). iNOS Ϫ/Ϫ and wild type CD2 and C57BL/6 mice were purchased from The Jackson Laboratory (Bar Harbor, ME).…”

Section: Methodsmentioning

confidence: 99%

“…This effect was specific to NF-B as IB␣-SR-expressing muscles displayed lower levels of NF-B transcriptional activity (supplemental Fig. 2B) as measured by NF-B reporter mice (3xB-Luc-Tg) (29). Myofiber counts were also performed in muscles from young mice conditionally lacking IKK␤ (24 -26).…”

Section: Nf-b Regulates Myogenesis During Early Postnatalmentioning

confidence: 99%

NF-κB Functions in Stromal Fibroblasts to Regulate Early Postnatal Muscle Development

Dahlman

Bakkar

et al. 2010

Journal of Biological Chemistry

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Classical NF-B activity functions as an inhibitor of the skeletal muscle myogenic program. Recent findings reveal that even in newborn RelA/p65 ؊/؊ mice, myofiber numbers are increased over that of wild type mice, suggesting that NF-B may be a contributing factor in early postnatal skeletal muscle development. Here we show that in addition to p65 deficiency, repression of NF-B with the IB␣-SR transdominant inhibitor or with muscle-specific deletion of IKK␤ resulted in similar increases in total fiber numbers as well as an up-regulation of myogenic gene products. Upon further characterization of early postnatal muscle, we observed that NF-B activity progressively declines within the first few weeks of development. At birth, the majority of this activity is compartmentalized to muscle fibers, but by neonatal day 8 NF-B activity from the myofibers diminishes, and instead, stromal fibroblasts become the main cellular compartment within the muscle that contains active NF-B. We find that NF-B functions in these fibroblasts to regulate inducible nitric-oxide synthase expression, which we show is important for myoblast fusion during the growth and maturation process of skeletal muscle. Together, these data broaden our understanding of NF-B during development by showing that in addition to its role as a negative regulator of myogenesis, NF-B also regulates nitric-oxide synthase expression within stromal fibroblasts to stimulate myoblast fusion and muscle hypertrophy.

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“…In the Il-10 -/-model of colitis, NF-κB activation is thought to contribute to intestinal inflammation by acting in mucosal immune cells rather than in epithelial cells. Using an elegant NF-κB-driven EGFP reporter gene transgenic mouse model, Karrasch et al [20] showed that upregulation of NF-κB activity during colitis onset in Il-10 -/-mice follows distinct kinetics in IECs versus mucosal immune cells. Colonization of germ-free Il-10 -/-mice, which do not develop colitis [21], with colitogenic bacteria induced colitis associated with rapid and transient activation of NF-κB in IECs, while lamina propria immune cells displayed delayed but more persistent NF-κB activation [20].…”

Section: Detrimental Role For Nf-κb Activation In the Intestinementioning

confidence: 99%

“…Using an elegant NF-κB-driven EGFP reporter gene transgenic mouse model, Karrasch et al [20] showed that upregulation of NF-κB activity during colitis onset in Il-10 -/-mice follows distinct kinetics in IECs versus mucosal immune cells. Colonization of germ-free Il-10 -/-mice, which do not develop colitis [21], with colitogenic bacteria induced colitis associated with rapid and transient activation of NF-κB in IECs, while lamina propria immune cells displayed delayed but more persistent NF-κB activation [20]. NF-κB inhibition by conditional ablation of IKK2 in IECs did not alter colitis incidence or severity, while IKK2 ablation in myeloid cells diminished colitis occurrence in Il-10 -/-mice [22], demonstrating that NF-κB activation in myeloid cells has an important role for the induction of colon inflammation in this model.…”

Section: Detrimental Role For Nf-κb Activation In the Intestinementioning

confidence: 99%

NF-κB in the regulation of epithelial homeostasis and inflammation

2010

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The IκB kinase/NF-κB signaling pathway has been implicated in the pathogenesis of several inflammatory diseases. Increased activation of NF-κB is often detected in both immune and non-immune cells in tissues affected by chronic inflammation, where it is believed to exert detrimental functions by inducing the expression of proinflammatory mediators that orchestrate and sustain the inflammatory response and cause tissue damage. Thus, increased NF-κB activation is considered an important pathogenic factor in many acute and chronic inflammatory disorders, raising hopes that NF-κB inhibitors could be effective for the treatment of inflammatory diseases. However, ample evidence has accumulated that NF-κB inhibition can also be harmful for the organism, and in some cases trigger the development of inflammation and disease. These findings suggested that NF-κB signaling has important functions for the maintenance of physiological immune homeostasis and for the prevention of inflammatory diseases in many tissues. This beneficial function of NF-κB has been predominantly observed in epithelial cells, indicating that NF-κB signaling has a particularly important role for the maintenance of immune homeostasis in epithelial tissues. It seems therefore that NF-κB displays two faces in chronic inflammation: on the one hand increased and sustained NF-κB activation induces inflammation and tissue damage, but on the other hand inhibition of NF-κB signaling can also disturb immune homeostasis, triggering inflammation and disease. Here, we discuss the mechanisms that control these apparently opposing functions of NF-κB signaling, focusing particularly on the role of NF-κB in the regulation of immune homeostasis and inflammation in the intestine and the skin.

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Gnotobiotic IL-10−/−;NF-κBEGFP Mice Reveal the Critical Role of TLR/NF-κB Signaling in Commensal Bacteria-Induced Colitis

Cited by 109 publications

References 67 publications

Mu Opioid Signaling Protects Against Acute Murine Intestinal Injury in a Manner Involving Stat3 Signaling

Mu Opioid Signaling Protects Against Acute Murine Intestinal Injury in a Manner Involving Stat3 Signaling

NF-κB Functions in Stromal Fibroblasts to Regulate Early Postnatal Muscle Development

NF-κB in the regulation of epithelial homeostasis and inflammation

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