Interleukin-11 Reduces TLR4-Induced Colitis in TLR2-Deficient Mice and Restores Intestinal STAT3 Signaling

Gibson, Deanna L.; Montero, Marinieve; Ropeleski, Mark J.; Bergstrom, Kirk; Ma, Cun‐Gen; Ghosh, Sanjoy; Merkens, Helen; Huang, Jingtian; Månsson, Lisa; Sham, Ho Pan; McNagny, Kelly M.; Vallance, Bruce A.

doi:10.1053/j.gastro.2010.06.057

Cited by 63 publications

(55 citation statements)

References 29 publications

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“…Strong STAT3 activation in IECs is also found upon infection with C. rodentium (49). Thus, our data support a model in which STAT3 activation in CD4 + lymphocytes links STAT3 activation in IECs via IL-22, thereby shaping the host defense in the colon during infection with enteropathogenic bacteria.…”

Section: Discussionsupporting

confidence: 81%

STAT3 Activation in Th17 and Th22 Cells Controls IL-22–Mediated Epithelial Host Defense during Infectious Colitis

Backert

Koralov

Wirtz

et al. 2014

The Journal of Immunology

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The Citrobacter rodentium model mimics the pathogenesis of infectious colitis and requires sequential contributions from different immune cell populations, including innate lymphoid cells (ILCs) and CD4+ lymphocytes. In this study, we addressed the role of STAT3 activation in CD4+ cells during host defense in mice against C. rodentium. In mice with defective STAT3 in CD4+ cells (Stat3ΔCD4), the course of infection was unchanged during the innate lymphoid cell–dependent early phase, but significantly altered during the lymphocyte-dependent later phase. Stat3ΔCD4 mice exhibited intestinal epithelial barrier defects, including downregulation of antimicrobial peptides, increased systemic distribution of bacteria, and prolonged reduction in the overall burden of C. rodentium infection. Immunomonitoring of lamina propria cells revealed loss of virtually all IL-22–producing CD4+ lymphocytes, suggesting that STAT3 activation was required for IL-22 production not only in Th17 cells, but also in Th22 cells. Notably, the defective host defense against C. rodentium in Stat3∆CD4 mice could be fully restored by specific overexpression of IL-22 through a minicircle vector–based technology. Moreover, expression of a constitutive active STAT3 in CD4+ cells shaped strong intestinal epithelial barrier function in vitro and in vivo through IL-22, and it promoted protection from enteropathogenic bacteria. Thus, our work indicates a critical role of STAT3 activation in Th17 and Th22 cells for control of the IL-22–mediated host defense, and strategies expanding STAT3-activated CD4+ lymphocytes may be considered as future therapeutic options for improving intestinal barrier function in infectious colitis.

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Section: Discussionsupporting

confidence: 81%

STAT3 Activation in Th17 and Th22 Cells Controls IL-22–Mediated Epithelial Host Defense during Infectious Colitis

Backert

Koralov

Wirtz

et al. 2014

The Journal of Immunology

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“…Cell type specificity of TLR5 signaling likely plays a role in its differential outcomes for the host. Similarly, hypersensitivity of Tlr2 -/-mice to Citrobacter rodentium-induced colitis is rescued by additional TLR4 deficiency [57]. Interestingly, bone marrow transfer experiments performed in this study showed that TLR4 signaling in hematopoietic cells causes lethality, while TLR2 signaling in tissue-resident cells mediates mucosal healing during infection.…”

Section: Mechanisms Underlying the Dual Role Of Intestinal Nf-κb Actimentioning

confidence: 51%

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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“…Therefore IL-11 was examined on experimental colitis in the rat induced by trinitrobenzene sulfonic acid (TNBS), where IL-11 exerted protective effect [302]. Recent findings confirmed the beneficial action of IL-11: administration of exogenous IL-11 was found to be protective against lethal colitis in TLR2-deficient mice (TLR2 is involved in maintaining epithelial barrier function) [303]. However, in a human study recombinant human IL-11 was less effective than prednisolone in the treatment of CD [304].…”

Section: Il-11mentioning

confidence: 98%

Gut Inflammation: Current Update on Pathophysiology, Molecular Mechanism and Pharmacological Treatment Modalities

Gyires¹,

Tóth²,

Zádori

2014

CPD

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Inflammatory bowel disease (IBD) is a chronic and relapsing inflammatory condition of the gastrointestinal tract. The two main forms of IBD are Crohn's disease and ulcerative colitis. According to the recent concept the disease is caused by a combination of factors, including genetics, immune dysregulation, barrier dysfunction and the change in microbial flora. Environmental factors, such as changes in diet, antibiotic use, smoking or improved domestic hygiene (e.g. eradication of intestinal helminths) probably contribute to the development and increased prevalence of IBD. Dysregulation of mucosal immunity in IBD causes an overproduction of inflammatory cytokines which resulted in uncontrolled intestinal inflammation. Based on extensive research over the last decade, besides the conventional therapy, there are several novel pathways and specific targets, on which focus new therapeutics. New therapeutics aim 1./ to correct genetic susceptibility by stimulating NOD2 expression, TLR3 signaling or inhibition of TLR4 pathway, 2./ to restore the immune dysregulation by inhibition of pro-inflammatory cytokines (TNF-, IL-6, IL-13, IL-17, IL-18, IL-21), Th1 polarisation (IL-2, IL-12, IL-23, IFN-), T-cell activation, leukocyte adhesion, as well as by immunostimulation (GM-CSF, G-CSF) and anti-inflammatory cytokines (IL-10, IL-11, IFN--1a), 3./ to restore mucosal barrier function and stimulate mucosal healing by different growth factors, such as GH, EGF, KGF, TGF-, VEGF, 4./ to restore the normal bacterial flora by antibiotics, probiotics. However, in spite of these numerous potential targets, the true value and clinical significance of most of the new biologics and molecules are not clear yet.

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Interleukin-11 Reduces TLR4-Induced Colitis in TLR2-Deficient Mice and Restores Intestinal STAT3 Signaling

Cited by 63 publications

References 29 publications

STAT3 Activation in Th17 and Th22 Cells Controls IL-22–Mediated Epithelial Host Defense during Infectious Colitis

STAT3 Activation in Th17 and Th22 Cells Controls IL-22–Mediated Epithelial Host Defense during Infectious Colitis

NF-κB in the regulation of epithelial homeostasis and inflammation

Gut Inflammation: Current Update on Pathophysiology, Molecular Mechanism and Pharmacological Treatment Modalities

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