Intracellular production of interleukin-18 in human epithelial-like cell lines is enhanced by hyperosmotic stress in vitro

IL-18 and IL-18 binding protein (IL-18BP) are two newly described opponents in the cytokine network. Local concentrations of these two players may determine biological functions of IL-18 in the context of inflammation, infection, and cancer. As IL-18 appears to be involved in the pathogenesis of Crohn’s disease and may modulate tumor growth, we investigated the IL-18/IL-18BPa system in the human colon carcinoma/epithelial cell line DLD-1. In this study, we report that IFN-γ induces expression and release of IL-18BPa from DLD-1 cells. mRNA induction and secretion of IL-18BPa immunoreactivity were associated with an activity that significantly impaired release of IFN-γ by IL-12/IL-18-stimulated PBMC. Inducibility of IL-18BPa by IFN-γ was also observed in LoVo, Caco-2, and HCT116 human colon carcinoma cell lines and in the human keratinocyte cell line HaCaT. Induction of IL-18BPa in colon carcinoma/epithelial cell lines was suppressed by coincubation with sodium butyrate. IFN-γ-mediated IL-18BPa and its suppression by sodium butyrate were confirmed in organ cultures of intestinal colonic biopsy specimens. In contrast, sodium butyrate did not modulate expression of IL-18. The present data suggest that IFN-γ may limit biological functions of IL-18 at sites of colonic immune activation by inducing IL-18BPa production. Down-regulation of IL-18BPa by sodium butyrate suggests that reinforcement of local IL-18 activity may contribute to actions of this short-chain fatty acid in the colonic microenvironment.

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“…Crohn's disease (12,13). Interestingly, reduction of IL-18 bioactivity by neutralizing Abs is protective in murine experimental colitis (14).…”

Section: Colon Epithelial Cells Have Been Identified As a Potential Smentioning

confidence: 99%

Expression and Release of IL-18 Binding Protein in Response to IFN-γ

Paulukat

Bosmann

Nold

et al. 2001

The Journal of Immunology

124

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“…IL-12 mRNA was decreased in experimental NEC (10). Although IL-18 has not previously been studied in NEC, its constitutive production by murine fetal and adult IEC (25) and increased production in human epithelial cell lines subjected to hyperosmotic stress (29) suggest its potential as a mediator of tissue damage in NEC.…”

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confidence: 94%

Up-Regulation of IL-18 and IL-12 in the Ileum of Neonatal Rats with Necrotizing Enterocolitis

et al. 2002

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Necrotizing enterocolitis (NEC) is a common and devastating gastrointestinal disease of premature infants. Because the proinflammatory cytokines IL-18, IL-12, and interferon (IFN)-␥ have been implicated in other diseases of the small intestine, we hypothesized that these cytokines would play an important role in NEC pathogenesis. NEC was induced in newborn rats via enteral feeding with rat milk substitute and asphyxia and cold stress (RMS). Dam-fed, asphyxia-and cold-stressed littermates were used as controls (DF). After 96 h, the distal ileum was removed from all animals and processed to determine expression and localization of IL-18, IL-12, and IFN-␥ using real-time reverse transcriptase PCR and immunohistology. IL-18 and IL-12 mRNA from the RMS group were increased (p Յ 0.05) compared with DF controls, and there was a correlation between increasing IL-18 and IL-12 mRNA levels and progression of tissue damage (r ϭ 0.629 and 0.588, respectively; p Յ 0.05). NEC is the most common gastrointestinal disease of premature infants (1). Its etiology, however, remains elusive (2). It has been suggested that the major risk factors for NECprematurity, formula feeding, intestinal ischemia/hypoxia, and bacterial colonization-promote an inflammatory cascade that results in the pathology associated with this disease (3, 4). The development of animal models has been vital to the understanding of NEC (5). The neonatal rat model, where NEC is induced in newborn rats by enteral feeding of artificial formula coupled with asphyxia and cold stress, is an established model for study of this disease (6 -11).The intestinal environment is capable of producing an array of cytokines important in the development and control of inflammatory responses (12, 13). Among these, proinflammatory IL-18 (14 -17), , and IFN-␥ (21, 22) have been implicated in inflammatory diseases of the small intestine. Individually, IL-18 and IL-12 can induce small amounts of IFN-␥ from T, natural killer (NK), and B cells. Together, IL-18 and IL-12 can work synergistically to induce greater quantities of IFN-␥ from these immunocompetent cells, and IL-18 and IL-12 can induce intestinal inflammation in the presence of IFN-␥ in mice (23). Both IL-18 and IL-12 are produced by MC, however, IL-18 is produced by IEC as well (12, 24 -26).Cytokine profiles in NEC are poorly defined and sometimes contradictory. IFN-␥ mRNA showed a slight trend toward up-regulation in rats with experimental NEC (10) and was increased in infants with NEC (27, 28

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“…The translation-starting site is present in exon 2. 18 Two promoter regions of the hIL-18 have been reported, one of which is located within the 6.7 kb region upstream of exon 2 19 and the other in the 5 0 -flanking region. 18 This 6.7 kb region includes recognition sites such as PU.1 (purine-rich sequence), NF-kB (nuclear factor), AP1 (activator protein) and Sp-1 (specificity protein).…”

Section: Introductionmentioning

confidence: 99%

Association between adult-onset Still's disease and interleukin-18 gene polymorphisms

et al. 2002

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Recently, we reported that serum concentration of IL-18 is strikingly high in patients with adult-onset Still's disease (AOSD). The aim of the present study was to screen for genetic polymorphisms in the human IL-18 (hIL-18) gene and to determine the association of polymorphisms with susceptibility to AOSD. We investigated the 6.7 kb region upstream of exon 2 of hIL-18 gene, in which a promoter activity had been reported. Sixteen AOSD patients, 144 rheumatoid arthritis (RA) patients and 92 healthy control individuals were studied. We found seven single nucleotide polymorphisms and a single 9 bp insertion which were frequently present in the AOSD patients. Three haplotypes including a unique combination of these polymorphisms were also determined. Of them, haplotype S01 contained all eight of these polymorphisms. The frequency of individuals carrying a diplotype configuration, ie a combination of two haplotypes, of S01/S01 was significantly higher in the AOSD patients than in the healthy controls (P ¼ 0.00059, Fischer's exact probability test, odds ratio [OR] ¼ 7.81, 95% confidence interval [95% CI] ¼ 2. 48-24.65) and the RA patients (P ¼ 0.015, Fischer's exact probability test, OR ¼ 4.0, 95% CI ¼ 1.39-11.54). We therefore conclude that possession of the diplotype configuration of S01/S01 is a major genetic risk factor for susceptibility to AOSD.

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Intracellular production of interleukin-18 in human epithelial-like cell lines is enhanced by hyperosmotic stress in vitro

Cited by 56 publications

References 28 publications

Expression and Release of IL-18 Binding Protein in Response to IFN-γ

Expression and Release of IL-18 Binding Protein in Response to IFN-γ

Up-Regulation of IL-18 and IL-12 in the Ileum of Neonatal Rats with Necrotizing Enterocolitis

Association between adult-onset Still's disease and interleukin-18 gene polymorphisms

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