Cutting Edge: IL-23 Cross-Regulates IL-12 Production in T Cell-Dependent Experimental Colitis

Becker, Christoph; Dornhoff, Heike; Neufert, Clemens; Fantini, Massimo; Wirtz, Stefan; Huebner, Sabine; Nikolaev, Alexei; Lehr, Hans‐Anton; Murphy, Andrew J.; Valenzuela, David M.; Yancopouloš, George D.; Galle, Peter R.; Karow, Margaret; Neurath, Markus F.

doi:10.4049/jimmunol.177.5.2760

Cited by 213 publications

(152 citation statements)

References 22 publications

Supporting

Mentioning

142

Contrasting

Unclassified

Order By: Relevance

“…Second, IL-17 produced by Th17 cells as they accumulate at the site of inflammation may negatively regulate the recruitment of Th1 cells. Consistent with the notion of a feedback loop in which IL-23 and IL-17 negatively regulate the IL-12/IFN-␥ network, the administration of an anti-IL-17 mAb worsens the course of dextran sodium sulfate-induced colitis, the elimination of IL-23 worsens the development of T cell-mediated trinitrobenzene sulfonic acid-induced colitis, and donor Th17 cells negatively regulate Th1 differentiation and ameliorate acute graftvs-host disease (51)(52)(53). Similarly, in a mouse model of allergic asthma, IL-17 functions as a negative regulator by repressing expression of the eosinophil chemokine CCL11 (eotaxin) and the Th2 chemokine CCL17 (thymus-and activation-regulated chemokine or TARC) (27).…”

Section: Discussionmentioning

confidence: 54%

Differential Regulation of Chemokines by IL-17 in Colonic Epithelial Cells

Lee

Wang

Kattah³

et al. 2008

The Journal of Immunology

115

View full text Add to dashboard Cite

The IL-23/IL-17 pathway plays an important role in chronic inflammatory diseases, including inflammatory bowel disease. In inflammatory bowel disease, intestinal epithelial cells are an important source of chemokines that recruit inflammatory cells. We examined the effect of IL-17 on chemokine expression of HT-29 colonic epithelial cells. IL-17 strongly repressed TNF-α-stimulated expression of CXCL10, CXCL11, and CCL5, but synergized with TNF-α for induction of CXCL8, CXCL1, and CCL20 mRNAs. For CXCL10, IL-17 strongly inhibited promoter activity but had no effect on mRNA stability. In contrast, for CXCL8, IL-17 slightly decreased promoter activity but stabilized its normally unstable mRNA, leading to a net increase in steady-state mRNA abundance. IL-17 synergized with TNF-α in transactivating the epidermal growth factor receptor (EGFR) and in activating ERK and p38 MAPK. The p38 and ERK pathway inhibitors SB203580 and U0126 reversed the repressive effect of IL-17 on CXCL10 mRNA abundance and promoter activity and also reversed the inductive effect of IL-17 on CXCL8 mRNA, indicating that MAPK signaling mediates both the transcriptional repression of CXCL10 and the stabilization of CXCL8 mRNA by IL-17. The EGFR kinase inhibitor AG1478 partially reversed the effects of IL-17 on CXCL8 and CXCL10 mRNA, demonstrating a role for EGFR in downstream IL-17 signaling. The overall results indicate a positive effect of IL-17 on chemokines that recruit neutrophils (CXCL8 and CXCL1), and Th17 cells (CCL20). In contrast, IL-17 represses expression of CXCL10, CXCL11, and CCR5, three chemokines that selectively recruit Th1 but not other effector T cells.

show abstract

Section: Discussionmentioning

confidence: 54%

Differential Regulation of Chemokines by IL-17 in Colonic Epithelial Cells

Lee

Wang

Kattah³

et al. 2008

The Journal of Immunology

115

View full text Add to dashboard Cite

show abstract

“…More important, the production of IL-12 was higher in p19 -/-DC and that of IL-23 higher in p35 -/-DC, and both cytokines were cross-regulated in WT DC. These findings suggest that these cytokines are reciprocally regulated at the level of DC production [34]. However, because inflammatory DC more than tolerogenic DC appear to produce IL-23 in response to fungi, this implies that the Th1/Th17 balance also depends on the reciprocal regulation between DC subsets at different body sites.…”

Section: Discussionmentioning

confidence: 98%

IL‐23 and the Th17 pathway promote inflammation and impair antifungal immune resistance

et al. 2007

View full text Add to dashboard Cite

Although inflammation is an essential component of the protective response to fungi, its dysregulation may significantly worsen fungal diseases. We found here that the IL‐23/IL‐17 developmental pathway acted as a negative regulator of the Th1‐mediated immune resistance to fungi and played an inflammatory role previously attributed to uncontrolled Th1 cell responses. Both inflammation and infection were exacerbated by a heightened Th17 response against Candida albicans and Aspergillus fumigatus, two major human fungal pathogens. IL‐23 acted as a molecular connection between uncontrolled fungal growth and inflammation, being produced by dendritic cells in response to a high fungal burden and counter‐regulating IL‐12p70 production. Both IL‐23 and IL‐17 subverted the inflammatory program of neutrophils, which resulted in severe tissue inflammatory pathology associated with infection. Our data are the first demonstrating that the IL‐23/IL‐17 pathway promotes inflammation and susceptibility in an infectious disease model. As IL‐23‐driven inflammation promotes infection and impairs antifungal resistance, modulation of the inflammatory response represents a potential strategy to stimulate protective immune responses to fungi.See accompanying commentary: http://dx.doi.org/10.1002/eji.200737804

show abstract

“…Consistent with this, p19-knockout mice were also highly susceptible to 2,4,6-trinitrobenzene sulfonic acid colitis in comparison to both p35-knockout and wild-type mice. 38 Overall, these data indicate that Th17 and Th1 T cells mediate different types of colitis, as underscored by the different outcomes obtained by IL-23 / IL-12 blockade in different mice models. However, it is not possible at the moment to rule out the possibility that Th17 and Th1 immune responses might coexist, representing different stages of the same mucosal inflammatory process.…”

Section: Th17 Cells and Colitismentioning

confidence: 95%

IL-21 comes of age as a regulator of effector T cells in the gut

2008

View full text Add to dashboard Cite

In healthy individuals, antigens from the gut lumen are tolerated by the mucosal immune system. However, a loss of tolerance toward the bacterial microflora probably causes inflammatory bowel disease (IBD), Crohn ' s disease (CD) and ulcerative colitis. The abnormal activation of the immune system in the gut of IBD patients is characterized by a cascade of cellular events orchestrated by cytokine cross talk between immune and non-immune cells. Interleukin (IL)-21, the newest member of the common -chain-dependent cytokine family, is a key component of the inflammatory cascade in the gut. It is highly expressed in CD and sustains the ongoing T helper type 1 (Th1)-mediated immune response. IL-21 is essential for the differentiation of Th17 cells. IL-21 is also involved in recruiting T cells to the inflamed gut and eliciting the secretion of matrix-degrading enzymes by gut fibroblasts. Overall, there is now sufficient evidence to suggest that targeting IL-21 will be of therapeutic benefit in IBD.

show abstract

Cutting Edge: IL-23 Cross-Regulates IL-12 Production in T Cell-Dependent Experimental Colitis

Cited by 213 publications

References 22 publications

Differential Regulation of Chemokines by IL-17 in Colonic Epithelial Cells

Differential Regulation of Chemokines by IL-17 in Colonic Epithelial Cells

IL‐23 and the Th17 pathway promote inflammation and impair antifungal immune resistance

IL-21 comes of age as a regulator of effector T cells in the gut

Contact Info

Product

Resources

About