Cytokine production in patients with inflammatory bowel disease.

Nakamura, Masataka; Saito, Hirohisa; Kasanuki, Junji; Tamura, Yasuhiro; Yoshida, Shuzo

doi:10.1136/gut.33.7.933

Cited by 111 publications

(74 citation statements)

References 12 publications

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“…It has been proposed that the cytokine-induced increase in intestinal TJ permeability represents an important proinflammatory mechanism (14,26). The cytokine-induced increase in intestinal TJ permeability allows increased paracellular permeation of luminal Ags, bacteria, and other toxic substances that promote inflammation (10,11).…”

Section: Discussionmentioning

confidence: 99%

IL-1β Causes an Increase in Intestinal Epithelial Tight Junction Permeability

Al–Sadi

Thomas

2007

The Journal of Immunology

510

372

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IL-1β is a prototypical proinflammatory cytokine that plays a central role in the intestinal inflammation amplification cascade. Recent studies have indicated that a TNF-α- and IFN-γ-induced increase in intestinal epithelial paracellular permeability may be an important mechanism contributing to intestinal inflammation. Despite its central role in promoting intestinal inflammation, the role of IL-1β on intestinal epithelial tight junction (TJ) barrier function remains unclear. The major aims of this study were to determine the effect of IL-1β on intestinal epithelial TJ permeability and to elucidate the mechanisms involved in this process, using a well-established in vitro intestinal epithelial model system consisting of filter-grown Caco-2 intestinal epithelial monolayers. IL-1β (0–100 ng/ml) produced a concentration- and time-dependent decrease in Caco-2 transepithelial resistance. Conversely, IL-1β caused a progressive time-dependent increase in transepithelial permeability to paracellular marker inulin. IL-1β-induced increase in Caco-2 TJ permeability was accompanied by a rapid activation of NF-κB. NF-κB inhibitors, pyrrolidine dithiocarbamate and curcumin, prevented the IL-1β-induced increase in Caco-2 TJ permeability. To further confirm the role of NF-κB in the IL-1β-induced increase in Caco-2 TJ permeability, NF-κB p65 expression was silenced by small interfering RNA transfection. NF-κB p65 depletion completely inhibited the IL-1β-induced increase in Caco-2 TJ permeability. IL-1β did not induce apoptosis in the Caco-2 cell. In conclusion, our findings show for the first time that IL-1β at physiologically relevant concentrations causes an increase in intestinal epithelial TJ permeability. The IL-1β-induced increase in Caco-2 TJ permeability was mediated in part by the activation of NF-κB pathways but not apoptosis.

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Section: Discussionmentioning

confidence: 99%

IL-1β Causes an Increase in Intestinal Epithelial Tight Junction Permeability

Al–Sadi

Thomas

2007

The Journal of Immunology

510

372

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“…Several studies in Crohn's disease showed that mononuclear cells and macrophages isolated from the lamina propria expressed high levels of TNF-␣ (6, 41) and IL-1␤ (24,30,32). Inflamed colonic mucosa obtained from patients with active Crohn's disease spontaneously produced increased amounts of TNF-␣, IL-6, and IL-1␤ compared with normal mucosa (8,21,39,40).…”

Section: Discussionmentioning

confidence: 99%

Linoleic acid induces interleukin-8 production by Crohn's human intestinal smooth muscle cells via arachidonic acid metabolites

Alzoghaibi¹,

Walsh²,

Willey³

et al. 2004

American Journal of Physiology-Gastrointestinal and Liver Physi

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Previously we reported that linoleic acid (LA), but not oleic acid, caused a marked increase in the secretion of IL-8 by Crohn's human intestinal smooth muscle (HISM) cells. Antioxidants inhibited this response, implicating a role for oxidative stress and NF-κB, a transcription factor for IL-8 that is activated by oxidative stress. In this study, we examined two mechanisms whereby LA, the dietary precursor for arachidonic acid (AA), could increase the production of IL-8 via activation of AA pathways: 1) by generation of reactive oxygen species by the AA-pathway enzymes to activate NF-κB or 2) by AA metabolites. Normal and Crohn's HISM cells were exposed to LA, oxidizing solution (Ox), or oxidizing solution enriched with LA (OxLA). Exposure of cells to Ox or OxLA induced oxidative stress as determined by thiobarbituric acid reactive substances. In normal cells, Ox but not LA activated NF-κB as determined by transfection experiments and Western blot. In Crohn's cells, NF-κB was spontaneously activated and was not further activated by Ox or LA. In contrast, TNF-α markedly increased activation of NF-κB in both normal and Crohn's cells. These results indicated that LA did not increase IL-8 by activating NF-κB, so we evaluated the second mechanism of an effect of AA metabolites. In normal cells, OxLA, but not LA, markedly stimulated IL-8, whereas in Crohn's cells, both OxLA and LA stimulated IL-8. OxLA, also stimulated production of AA metabolites leukotriene B4(LTB4), PGE2, and thromboxane B2(TXB2) by normal and Crohn's cells. To determine whether AA metabolites mediated the IL-8 response, cells were treated with OxLA plus indomethacin (Indo), a cyclooxygenase inhibitor, and nordihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor. Both Indo and NDGA blocked the IL-8 response to OxLA. To determine more specifically a role for AA metabolites, AA was used. Similar to OxLA, OxAA stimulated production of IL-8 and AA metabolites. Pinane thromboxane, a selective thromboxane synthase inhibitor and receptor blocker, inhibited OxAA stimulation of TXB2and IL-8 in a dose-response manner. MK886, a selective 5-lipoxygenase inhibitor, inhibited OxAA stimulation of LTB4and IL-8 also in a dose-response manner. Analysis of specific gene products by RT-PCR demonstrated that HISM cells expressed receptors for both thromboxane and LTB4. We conclude that AA metabolites mediated the IL-8 response to LA in HISM cells. Both cyclooxygenase and lipoxygenase pathways were involved. LA did not increase IL-8 by activating NF-κB, but NF-κB appeared to be involved, because LA increased IL-8 only in situations where NF-κB was activated, either spontaneously in Crohn's cells or by Ox in normal cells. We speculate that AA metabolites increased IL-8 production by enhancing NF-κB-dependent transcription of IL-8.

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“…The proteins encoded by the IL-1 a and IL-1/3 genes appear to play an important role in chronic IBD, since enhanced production of IL-1 has been reported in gut tissue of animal models of intestinal inflammation [13,14], as well as in the mucosa [15] and isolated cell preparations of patients with active IBD [16,17].…”

Section: Introductionmentioning

confidence: 99%

Allelic polymorphism in IL-1β and IL-1 receptor antagonist (IL-1Ra) genes in inflammatory bowel disease

Bioque

Crusius

Koutroubakis

et al. 1995

Clinical and Experimental Immunology

185

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SUMMARY Recent reports have shown that allele 2 of the IL‐1 receptor antagonist (IL‐1Ra) gene is over‐represented in ulcerative colitis (UC). Healthy individuals carrying allele 2 of this gene have increased production of IL‐1Ra protein. Since the final outcome of the biological effects of IL‐1β may depend on the relative proportion of these two cytokines, we have studied if a TaqI polymorphism in the IL‐1β gene, which is relevant to IL‐1β protein production, may be involved in the genetic susceptibility to UC and Crohn's disease (CD), in association with the established IL‐1Ra gene polymorphism. Polymorphisms in the closely linked genes for IL‐1β and IL‐1Ra were typed in 100 unrelated Dutch patients with UC, 79 with CD, and 71 healthy controls. The polymorphic regions in exon 5 of the IL‐1β gene and in intron 2 of the IL‐1Ra gene, were studied by polymerase chain reaction (PCR)‐based methods. The IL‐1β allele frequencies in UC and CD patients did not differ from those in healthy controls. In order to study if the IL‐1β gene polymorphism might participate synergistically with the IL‐1Ra gene polymorphism in susceptibility to UC and CD, individuals were distributed into carriers and non‐carriers of allele 2 of the genes encoding IL‐1β and IL‐1Ra, in each of the patient groups and controls. Results indicated a significant association of this pair of genes, estimated by the odds ratio (OR) after performing Fisher's exact test, in the UC group (P= 0·023, OR = 2·81), as well as in the CD group (P= 0·01, OR = 3·79). Thus, non‐carriers of IL‐1β allele 2 were more often present in the subgroup of patients carrying the IL‐1Ra allele 2. By contrast, no association of these alleles was detected in the group of healthy controls (P= 1·00, OR = 0·92). These results suggest that the IL‐1β/IL‐1Ra allelic cluster may participate in defining the biological basis of predisposition to chronic inflammatory bowel diseases.

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Cytokine production in patients with inflammatory bowel disease.

Abstract: The production of cytokines in peripheral blood mononuclear leukocytes of patients with inflammatory bowel disease was investigated. T cell subset analysis and differential white blood cell counts were also performed.

Cited by 111 publications

References 12 publications

IL-1β Causes an Increase in Intestinal Epithelial Tight Junction Permeability

IL-1β Causes an Increase in Intestinal Epithelial Tight Junction Permeability

Linoleic acid induces interleukin-8 production by Crohn's human intestinal smooth muscle cells via arachidonic acid metabolites

Allelic polymorphism in IL-1β and IL-1 receptor antagonist (IL-1Ra) genes in inflammatory bowel disease

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