Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: Evidence in Crohn disease and experimental colitis in vivo

Atreya, Raja; Mudter, Jonas; Finotto, Susetta; Mullberg, Jürgen; Jostock, Thomas; Wirtz, Stefan; Schutz, M.M.; Bartsch, Brigitte; Holtmann, Martin; Becker, Christoph; Strand, Dennis; Czaja, J; Schlaak, Joerg F.; Lehr, Hans A.; Autschbach, Frank; Schürmann, G.; Nishimoto, Norihiro; Yoshizaki, Kazuyuki; Ito, Hiroaki; Kishimoto, Tadamitsu; Galle, Peter R.; Rose-John, Stefan; Neurath, Markus F.

doi:10.1038/75068

Cited by 1,156 publications

(721 citation statements)

References 25 publications

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“…Yang et al have reported that the intestinal barrier integrity is preserved in the IL-6 knock-out mice after hemorrhagic shock and resuscitation (35). Further, the knock-out and blockade of IL-6 and IL-6 receptor suppress experimental colitis in mice (21)(22)(23)(24). In agreement with the latter studies, our results suggest that IL-6 contributes to the intestinal barrier defect in IBD patients in concert with the other cytokines mentioned above.…”

Section: Discussionsupporting

confidence: 82%

“…IL-6 is produced in substantially higher amounts in both the serum and tissues of IBD patients. In mice, the knock-out and blockade of IL-6 and IL-6 receptor suppress experimental colitis, indicating an important contribution of IL-6 and the IL-6 trans-signaling pathways for progression of IBD (21)(22)(23)(24). The major source of IL-6 seen in IBD has been shown to be intestinal epithelial cells and lamina propria mononuclear cells (18).…”

mentioning

confidence: 99%

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Interleukin-6 (IL-6) Regulates Claudin-2 Expression and Tight Junction Permeability in Intestinal Epithelium

Suzuki

Yoshinaga

Tanabe

2011

Journal of Biological Chemistry

428

366

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In inflammatory bowel diseases (IBD), intestinal barrier function is impaired as a result of deteriorations in epithelial tight junction (TJ) structure. IL-6, a pleiotropic cytokine, is elevated in IBD patients, although the role of IL-6 in barrier function remains unknown. We present evidence that IL-6 increases TJ permeability by stimulating the expression of channel-forming claudin-2, which is required for increased caudal-related homeobox (Cdx) 2 through the MEK/ERK and PI3K pathways in intestinal epithelial cells. IL-6 increases the cation-selective TJ permeability without any changes to uncharged dextran flux or cell viability in Caco-2 cells. IL-6 markedly induces claudin-2 expression, which is associated with increased TJ permeability. The colonic mucosa of mice injected with IL-6 also exhibits an increase in claudin-2 expression. The claudin-2 expression and TJ permeability induced by IL-6 are sensitive to the inhibition of gp130, MEK, and PI3K. Furthermore, expression of WT-MEK1 induces claudin-2 expression in Caco-2 cells. Claudin-2 promoter activity is increased by IL-6 in a MEK/ERK and PI3K-dependent manner, and deletion of Cdx binding sites in the promoter sequence results in a loss of IL-6-induced promoter activity. IL-6 increases Cdx2 protein expression, which is suppressed by the inhibition of MEK and PI3K. These observations may reveal an important mechanism by which IL-6 can undermine the integrity of the intestinal barrier.

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Section: Discussionsupporting

confidence: 82%

mentioning

confidence: 99%

Interleukin-6 (IL-6) Regulates Claudin-2 Expression and Tight Junction Permeability in Intestinal Epithelium

Suzuki

Yoshinaga

Tanabe

2011

Journal of Biological Chemistry

428

366

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“…While IL6 is considered a proinflammatory cytokine, it has protective roles in early acute inflammation and shock through the modulation of other pro-inflammatory cytokines (Barton & Jackson 1993, Xing et al 1998, Diao & Kohanawa 2005 and the induction of inflammatory modulating cytokines, such as IL1RN (Tilg et al 1994). In addition to the resolution of acute inflammation, IL6 and its receptor has been suggested to have implications in the transition from innate to acquired immunity and the persistence of chronic inflammation (Kishimoto et al 1995, Atreya et al 2000, Jones 2005. It is possible that the increase in IL6 mRNA 6 h after insemination in resistant mares compared with susceptible mares may reflect initial inflammatory modulating roles of IL6 (similar to those of IL10 and IL1RN) during this time (Tilg et al 1994).…”

Section: Discussionmentioning

confidence: 99%

Endometrial inflammatory markers of the early immune response in mares susceptible or resistant to persistent breeding-induced endometritis

Woodward¹,

Christoffersen²,

Campos³

et al. 2013

Reproduction

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Transient endometritis after breeding is necessary for clearance of bacteria and spermatozoa; however, in a subpopulation of mares, the inflammation fails to resolve in a timely fashion. The objective of this study was to describe the uterine inflammatory response in mares susceptible or resistant to persistent breeding-induced endometritis (PBIE) during the first 24 h after induction of uterine inflammation. Twelve mares were classified as susceptible (nZ6) or resistant (nZ6) to PBIE. Mares were inseminated over five estrous cycles and endometrial biopsies were collected at one time point per cycle before (0) and 2, 6, 12, and 24 h after insemination. qPCR analysis for IL1B, IL6, IL8, IFNG, TNF (TNFA), IL10, and IL1RN was performed, and endometrial inflammatory cells were counted for each sample. Relative quantification values reported fold changes in mRNA expression from 0 h values. A general pattern of expression post insemination was observed in both groups of mares. Cytokine mRNA increased at 2 h, peaked between 2 and 12 h, and then decreased. Differences were detected between groups of mares 6 h after challenge; resistant mares had higher mRNA expression of IL6, IL1RN, and IL10 than susceptible mares. Susceptible mares had an increased number of polymorphonuclear neutrophils in the endometrium 2 and 12 h after breeding when compared with resistant mares. These findings describe an inherent difference in the initial immune response to insemination and may help explain the transient nature of inflammation in resistant mares, whereas susceptible mares develop a persistent inflammation.

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“…Atreya et al 49) and Yamamoto et al 50) reported that anti-IL-6R antibody suppressed the development of experimental colitis in mice, such as TNBS-induced, IL-10 knockout-induced, and CD45RBhigh CD4ϩ T cell-induced colitis. In mice treated with anti-IL-6R antibody, apoptosis of mucosal T cells was observed, suggesting that IL-6 might contribute to the survival of autoreactive T cells.…”

Section: Pathogenic Roles Of Il-6 In the Develop-ment Of Autoimmune Dmentioning

confidence: 99%

Recent Advances in Immunopathophysiology of Interleukin-6: An Innovative Therapeutic Drug, Tocilizumab (Recombinant Humanized Anti-human Interleukin-6 Receptor Antibody), Unveils The Mysterious Etiology of Immune-Mediated Inflammatory Diseases

Ohsugi

2007

Biological & Pharmaceutical Bulletin

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Interleukin (IL)-6 cDNA was originally cloned as a terminal B cell differentiation factor into antibody-producing plasma cells. This revealed that it is a multifunctional cytokine that acts on a variety of cells. From the clinical viewpoint, it is especially important that IL-6 acts on hepatocytes to induce acute-phase reactants, including C-reactive protein, serum amyloid A protein, and fibrinogen, and to decrease serum albumin levels. Very recently, this cytokine has been found to enhance the synthesis of a peptide called hepcidin in the liver which regulates iron recycling, resulting in anemia due to hypofferemia. It has also been shown that IL-6 is responsible for various clinical symptoms, including the appearance of autoantibodies, fatigue, anemia, anorexia, fever, and increases in the erythrocyte sedimentation rate, all of which develop in patients with various chronic autoimmune inflammatory diseases. In practice, blocking the IL-6 signaling pathway with a recombinant humanized anti-IL-6 receptor antibody, tocilizumab (TCZ), has dramatically improved all the signs and symptoms of these patients. A study in mice demonstrated that IL-6 promotes the development of a new type of T-helper cells called Th17 cells that impact the pathogenesis of autoimmune diseases. This suggests that TCZ is not only an antiinflammatory agent but also might affect basic autoimmunity. In this review, recent advances in the immunobiology of interleukin-6 related to immune-mediated diseases are discussed.

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Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: Evidence in Crohn disease and experimental colitis in vivo

Cited by 1,156 publications

References 25 publications

Interleukin-6 (IL-6) Regulates Claudin-2 Expression and Tight Junction Permeability in Intestinal Epithelium

Interleukin-6 (IL-6) Regulates Claudin-2 Expression and Tight Junction Permeability in Intestinal Epithelium

Endometrial inflammatory markers of the early immune response in mares susceptible or resistant to persistent breeding-induced endometritis

Recent Advances in Immunopathophysiology of Interleukin-6: An Innovative Therapeutic Drug, Tocilizumab (Recombinant Humanized Anti-human Interleukin-6 Receptor Antibody), Unveils The Mysterious Etiology of Immune-Mediated Inflammatory Diseases

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