Intestinal Interleukin-13 in Pediatric Inflammatory Bowel Disease Patients

Kadivar, Khadijeh; Ruchelli, Eduardo D.; Markowitz, Jonathan E.; DeFelice, Magee L.; Strogatz, Melissa; Kanzaria, Mitul; Reddy, K. Prudhvi; Baldassano, Robert N.; Allmen, Daniel von; Brown, Kenneth N.

doi:10.1097/00054725-200409000-00014

Cited by 39 publications

(31 citation statements)

References 23 publications

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“…This study also showed up-regulated mucosal TLR4 expression in patients with ulcerative colitis, which has recently been linked to atypical mucosal IL-13 expression (28,37). However, other studies described different mucosal Th cytokine profiles in patients with ulcerative colitis, ranging from diminished mucosal IL-13 expression (38,39) to increased IL-5 expression (40).…”

Section: Discussionsupporting

confidence: 59%

Th2 Cytokines Down-Regulate TLR Expression and Function in Human Intestinal Epithelial Cells

Müller

Takato

Rosenberg

et al. 2006

The Journal of Immunology

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TLRs serve important immune and nonimmune functions in human intestinal epithelial cells (IECs). Proinflammatory Th1 cytokines have been shown to promote TLR expression and function in IECs, but the effect of key Th2 cytokines (IL-4, IL-5, IL-13) on TLR signaling in IECs has not been elucidated so far. We stimulated human model IECs with Th2 cytokines and examined TLR mRNA and protein expression by Northern blotting, RT-PCR, real-time RT-PCR, Western blotting, and flow cytometry. TLR function was determined by I-κBα phosphorylation assays, ELISA for IL-8 secretion after stimulation with TLR ligands and flow cytometry for LPS uptake. IL-4 and IL-13 significantly decreased TLR3 and TLR4 mRNA and protein expression including the requisite TLR4 coreceptor MD-2. TLR4/MD-2-mediated LPS uptake and TLR ligand-induced I-κBα phosphorylation and IL-8 secretion were significantly diminished in Th2 cytokine-primed IECs. The down-regulatory effect of Th2 cytokines on TLR expression and function in IECs also counteracted enhanced TLR signaling induced by stimulation with the hallmark Th1 cytokine IFN-γ. In summary, Th2 cytokines appear to dampen TLR expression and function in resting and Th1 cytokine-primed human IECs. Diminished TLR function in IECs under the influence of Th2 cytokines may protect the host from excessive TLR signaling, but likely also impairs the host intestinal innate immune defense and increases IEC susceptibility to chronic inflammation in response to the intestinal microenvironment. Taken together, our data underscore the important role of Th2 cytokines in balancing TLR signaling in human IECs.

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Section: Discussionsupporting

confidence: 59%

Th2 Cytokines Down-Regulate TLR Expression and Function in Human Intestinal Epithelial Cells

Müller

Takato

Rosenberg

et al. 2006

The Journal of Immunology

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“…In our experiments however, the addition of rhIL-13 to unstimulated or anti-CD3/CD28-stimulated LPMCs from inflamed UC did not have any influence on their production of classical pro-inflammatory cytokines such as TNF-α, IFN-γ and IL-17A. The concentration of rhIL-13 that we used in our experiments (20 ng/mL) is tenfold higher than that reported to induce changes in epithelial permeability, and the same described to exert pro-fibrogenic effects, so we have no doubt that we added biologically active doses to the LPMCs [15,27], and this is confirmed by the up-regulation of claudin 2 expression induced by rhIL-13 in T84 cells. Since IL-13 and TNF-α can exert a synergistic effect on the expression of IL-13Rα2 and TNF-α has a known pro-fibrogenic action [17], we finally tested the effect of exogenous rhIL-13 and/or rhTNF-α on submucosal myofibroblasts isolated from CD strictures and control gut.…”

Section: Discussionmentioning

confidence: 67%

Absence of a role for interleukin‐13 in inflammatory bowel disease

et al. 2014

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IL-13 has been implicated in the pathogenesis of ulcerative colitis (UC), and may have a role in animal models of gut fibrosis. We studied the involvement of IL-13 in inflammation and fibrosis in UC and Crohn's disease (CD). Intestinal biopsies and anti-CD3/CD28-or anti-CD2/CD28-stimulated lamina propria mononuclear cells from UC and CD patients and control subjects were cultured, and IL-13, IL-4, IL-5, IL-17A and IFN-γ production was measured. Mucosal IL-13-producing cells were characterised by flow cytometry. Gut explants from strictured CD, non-strictured CD and healthy donors were cultured ex vivo, and secreted IL-13, IL-1β and collagen were measured. IL-13 production by mucosal explants and activated lamina propria mononuclear cells did not differ between CD, UC and control subjects, and was at least a log lower than IFN-γ and IL-17A. IL-13-producing cells, and in particular natural killer T cells, were uniformly low in all groups. IL-4 and IL-5 were undetectable in culture supernatants. Explants of CD strictures produced low amounts of IL-13, whereas IL-1β and collagen were elevated. We could not confirm that UC or strictured CD are associated with elevated IL-13 production. These data suggest that an anti-IL-13 Ab would not be an appropriate therapeutic strategy in inflammatory bowel disease. Keywords:Crohn's disease r Fibrosis r T helper cell type 2 r Ulcerative colitis Additional supporting information may be found in the online version of this article at the publisher's web-site Correspondence: Prof. Thomas T. MacDonald e-mail: t.t.macdonald@qmul.ac.uk * These authors contributed equally to this manuscript.C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2014. 44: 370-385 Cellular immune response 371 IntroductionCrohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory bowel disorders thought to be caused by an abnormal immune response against the normal microbial flora [1]. Until recent years, intestinal lesions in CD were thought to be the end result of a T helper cell type (Th)1 response, with overproduction of . However, more recently, two novel subsets of CD4 + T cells, namely Th17 cells, which produce the proinflammatory cytokine IL-17A, and Th1/Th17 cells, which release both IFN-γ and IL-17A, have been identified [3,4]. IL-17A is overexpressed in both CD and UC mucosa, and an increased number of Th17 and Th1/Th17 cells has been found in the lamina propria of inflammatory bowel disease patients compared with controls, suggesting that, in addition to Th1 cells, Th17 responses may play an important role in the pathogenesis of both CD and UC [5][6][7]. As opposed to CD, mucosal inflammation in UC is thought to be driven by Th2 cytokines, such as IL-5 and IL-13 [2]. IL-13 is a pleiotropic cytokine with effects on many cell types, including macrophages, epithelial cells, smooth muscle cells and neurons [8]. IL-13, produced by Th2 cells and CD1d-restricted natural killer T (NKT) cells, has been implicated in the pathogenesis of an UC-like model of...

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“…Our data suggest that claudin 2 was more highly expressed in UC (see Figure 4, Table 2) and it has recently been reported that mucosal T cells from UC patients make more IL-13 than T cells from normal patients or CD. 38 We hesitate to suggest that IL-13 is one of the mechanistic drivers of altered claudin 2 expression in IBD since the current literature on levels of IL-13 in IBD is contentious with studies showing both increased 38 and decreased levels 98,99 in disease. Our data from a cell culture model of the epithelial barrier indicate that one consequence of increased IL-13 would be to increase permeability, potentially involving increased claudin 2 expression, and that inflammatory cytokines may alter tight junctions via differential effects on claudin proteins.…”

Section: Inflammatory Cytokines and Claudin Expression S Prasad Et Almentioning

confidence: 99%

Inflammatory processes have differential effects on claudins 2, 3 and 4 in colonic epithelial cells

Prasad

Mingrino

Kaukinen

et al. 2005

Laboratory Investigation

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384

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Claudin proteins comprise a recently described family of tight junction proteins that differentially regulate paracellular permeability. Since other tight junction proteins show alterations in distribution or expression in inflammatory bowel disease (IBD) we assessed expression of claudins (CL) 2, 3 and 4 in IBD. CL 2 was strongly expressed along the inflamed crypt epithelium, whilst absent or barely detectable in normal colon. In contrast, CL 3 and 4 were present throughout normal colonic epithelium and were reduced or redistributed in the diseased surface epithelium. In a T84-cell culture model of the gut barrier, paracellular permeability decreased with time after plating and correlated with a marked decrease in the expression of CL 2. Addition of IFNc/TNFa led to further decreases in CL 2 and 3, the redistrbution of CL 4 and a marked increase in paracellular permeability. Conversely, IL-13 dramatically increased CL 2, with little effect on CL 3 or 4, but also resulted in increased paracellular permeability. Expression of CL 2 did not correlate with proliferation or junctional reorganisation after calcium ion depletion. Re-expression of CL 2 in response to IL-13 was inhibited by phophatidylinositol 3 kinase inhibitor, LY294002, which also restored the ion permeability to previous levels. CL 2 expression could be stimulated in the absence of IL-13 by activation of phospho-Akt in the phophatidylinositol 3 kinase pathway. These results suggest that INFc/TNFa and IL-13 have differential effects on CL 2, 3 and 4 in tight junctions, which may lead to increased permeability via different mechanisms.

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Intestinal Interleukin-13 in Pediatric Inflammatory Bowel Disease Patients

Abstract: Diminished intestinal IL-13 production is present in UC patients and wanes further with clinical disease progression. These findings suggest that UC patients may be differentiated from CD patients by intestinal IL-13 quantitation, and UC patients may benefit from IL-13 enhancing therapies.

Cited by 39 publications

References 23 publications

Th2 Cytokines Down-Regulate TLR Expression and Function in Human Intestinal Epithelial Cells

Th2 Cytokines Down-Regulate TLR Expression and Function in Human Intestinal Epithelial Cells

Absence of a role for interleukin‐13 in inflammatory bowel disease

Inflammatory processes have differential effects on claudins 2, 3 and 4 in colonic epithelial cells

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