Interleukin-6 Induces Keratin Expression in Intestinal Epithelial Cells

Wang, Lixin; Srinivasan, Shanthi; Theiss, Arianne L.; Merlin, Didier; Sitaraman, Shanthi V.

doi:10.1074/jbc.m604068200

Cited by 80 publications

(41 citation statements)

References 68 publications

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“…However, the role of IL-6 in the regulation of intestinal barrier is less unclear than those for other cytokines. Wang et al demonstrate that IL-6 suppresses the paracellular dextran flux in Caco-2 cells and that the IL-6 knock-out exacerbates the increased colonic permeability induced by the dextran sulfate sodium in mice (34). These data suggest that IL-6 may increase or protect the intestinal barrier integrity under some conditions.…”

Section: Discussionmentioning

confidence: 85%

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

Suzuki

Yoshinaga

Tanabe

2011

Journal of Biological Chemistry

451

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: Discussionmentioning

confidence: 85%

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

Suzuki

Yoshinaga

Tanabe

2011

Journal of Biological Chemistry

451

366

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“…Although the pro-inflammatory actions of IL-6 on immune system are well-described, the effects on intestinal epithelial barrier remain unclear. Previous studies by Wang et al found that IL-6 causes an enhancement of Caco-2 TJ barrier function through keratin-8 dependent mechanism [22], [42]. IL-6 caused a decrease in trans-epithelial flux of dextran (4 kd) and an increase in keratin-8 level, and inhibition of keratin-8 expression prevented the decrease in dextran-4 kd flux [22], [42].…”

Section: Discussionmentioning

confidence: 94%

Interleukin-6 Modulation of Intestinal Epithelial Tight Junction Permeability Is Mediated by JNK Pathway Activation of Claudin-2 Gene

et al. 2014

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Defective intestinal epithelial tight junction (TJ) barrier has been shown to be a pathogenic factor in the development of intestinal inflammation. Interleukin-6 (IL-6) is a pleiotropic, pro-inflammatory cytokine which plays an important role in promoting inflammatory response in the gut and in the systemic circulation. Despite its key role in mediating variety inflammatory response, the effect of IL-6 on intestinal epithelial barrier remains unclear. The purpose of this study was to investigate the effect of IL-6 on intestinal epithelial TJ barrier and to delineate the intracellular mechanisms involved using in-vitro (filter-grown Caco-2 monolayers) and in-vivo model (mouse intestinal perfusion) systems. Our results indicated that IL-6 causes a site-selective increase in Caco-2 intestinal epithelia TJ permeability, causing an increase in flux of small-sized molecules having molecular radius <4 Å. The size-selective increase in Caco-2 TJ permeability was regulated by protein-specific increase in claudin-2 expression. The IL-6 increase in TJ permeability required activation of JNK signaling cascade. The JNK pathway activation of AP-1 resulted in AP-1 binding to its binding sequence on the claudin-2 promoter region, leading to promoter activation and subsequent increase in claudin-2 gene transcription and protein synthesis and TJ permeability. Our in-vivo mouse perfusion showed that IL-6 modulation of mouse intestinal permeability was also mediated by AP-1 dependent increase in claudin-2 expression. In conclusion, our studies show for the first time that the IL-6 modulation of intestinal TJ permeability was regulated by JNK activation of AP-1 and AP-1 activation of claudin-2 gene.

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“…Intestinal permeability was measured in vivo to fluorescein isothiocyanate conjugated-dextran (FD-4, 22mg/ml, molecular mass 4.4 kDa) (9;34). Mice were gavaged with 0.5 ml of FD-4 19 hours following induction of pneumonia or sham pneumonia.…”

Section: Methodsmentioning

confidence: 99%

The Endogenous Bacteria Alter Gut Epithelial Apoptosis and Decrease Mortality Following Pseudomonas aeruginosa Pneumonia

Fox¹,

McConnell

Yoseph

et al. 2012

Shock

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The endogenous bacteria have been hypothesized to play a significant role in the pathophysiology of critical illness, although their role in sepsis is poorly understood. The purpose of this study was to determine how commensal bacteria alter the host response to sepsis. Conventional and germ free (GF) C57Bl/6 mice were subjected to Pseudomonas aeruginosa pneumonia. All GF mice died within two days while 44% of conventional mice survived for 7 days (p=0.001). Diluting the dose of bacteria 10-fold in GF mice led to similar survival in GF and conventional mice. When animals with similar mortality were assayed for intestinal integrity, GF mice had lower levels of intestinal epithelial apoptosis but similar levels of proliferation and intestinal permeability. GF mice had significantly lower levels of TNF and IL-1β in BAL fluid compared to conventional mice without changes in systemic cytokine production. Under conventional conditions, sepsis unmasks lymphocyte control of intestinal epithelial apoptosis, since sepsis induces a greater increase in gut apoptosis in Rag-1−/− mice than wild type (WT) mice. However, in a separate set of experiments, gut apoptosis was similar between septic GF Rag-1−/− mice and septic GF WT mice. These data demonstrate that the endogenous bacteria play a protective role in mediating mortality from pneumonia-induced sepsis, potentially mediated through altered intestinal apoptosis and the local pro-inflammatory response. Additionally, sepsis-induced lymphocyte-dependent increases in gut epithelial apoptosis appear to be mediated by the endogenous bacteria.

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Interleukin-6 Induces Keratin Expression in Intestinal Epithelial Cells

Cited by 80 publications

References 68 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

Interleukin-6 Modulation of Intestinal Epithelial Tight Junction Permeability Is Mediated by JNK Pathway Activation of Claudin-2 Gene

The Endogenous Bacteria Alter Gut Epithelial Apoptosis and Decrease Mortality Following Pseudomonas aeruginosa Pneumonia

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