Interferon-γ Mediates Gene Expression of IL-18 Binding Protein in Nonleukocytic Cells

Mühl, Heiko; Kämpfer, Heiko; Bosmann, Markus; Frank, Stefan; Radeke, Heinfried H.; Pfeilschifter, Josef

doi:10.1006/bbrc.1999.2064

Cited by 90 publications

(70 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We recently reported on induction of IL-18BPa gene expression by IFN-␥ in human nonleukocytic cells (19). In the present study, we focused on the colon carcinoma/epithelial cell line DLD-1 and sought to extend the abovementioned observations by including the level of IL-18BPa protein release and function.…”

Section: Ifn-␥ Induces Expression and Release Of Il-18bpa In The Colomentioning

confidence: 93%

See 1 more Smart Citation

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

Paulukat

Bosmann

Nold

et al. 2001

The Journal of Immunology

Self Cite

124

View full text Add to dashboard Cite

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.

show abstract

Section: Ifn-␥ Induces Expression and Release Of Il-18bpa In The Colomentioning

confidence: 93%

“…One microgram of RNA was used for RT-PCR (GeneAmp RNA PCR kit, Amplitaq Gold; Perkin-Elmer, Weiterstadt, Germany), as described previously (19 (19,20).…”

Section: Analysis Of Mrna For Il-18bpa Il-18 and Gapdhmentioning

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

Self Cite

124

View full text Add to dashboard Cite

show abstract

“…However, the activity of IL-18 is balanced by a naturally occurring IL-18 binding protein (IL-18BP). IFN-␥ stimulates the production of IL-18BP (13), prompting a classical feedback loop whereby IL-18BP neutralizes excessive IL-18 and attenuates the IFN-␥ response. Hyperferritinemia has recently been reported to be a common feature of dengue (14).…”

mentioning

confidence: 99%

Normal Free Interleukin-18 (IL-18) Plasma Levels in Dengue Virus Infection and the Need To Measure Both Total IL-18 and IL-18 Binding Protein Levels

Michels

Mast

Netea

et al. 2015

Clin Vaccine Immunol

View full text Add to dashboard Cite

bActivated monocytes/macrophages and T lymphocytes that produce a cytokine storm are assumed to play a pivotal role in the pathogenesis of dengue. Interleukin-18 (IL-18) is a proinflammatory cytokine that is increased during dengue and known to induce gamma interferon (IFN-␥), which is crucial for dengue immune response. No data are available regarding the balance between IL-18 and its natural inhibitor IL-18 binding protein (IL-18BP) and how they interact within the inflammatory reaction of patients with dengue virus infections. Circulating levels of IL-18; IL-18BP; free, biologically active IL-18; the IL-18-dependent proinflammatory cytokine IFN-␥; monocyte-derived cytokines; and ferritin were assessed in adult Indonesian dengue patients (n ‫؍‬ 95). Healthy individuals (n ‫؍‬ 22) and leptospirosis (n ‫؍‬ 19) and enteric fever (n ‫؍‬ 6) patients served as controls. Total IL-18 levels were increased during dengue, leptospirosis, and enteric fever compared to healthy controls. However, due to a concurrent increase in IL-18BP levels, biologically active IL-18 levels remained similar in the different phases of dengue and in patients with leptospirosis. Biologically active IL-18 levels were also similar in patients with severe and nonsevere dengue. In conclusion, high total IL-18 and IL-18BP levels concur in dengue virus infections, leptospirosis, and enteric fever. This resulted in unchanged levels of free, biologically active IL-18 in dengue and leptospirosis, which underlines the importance of measuring both IL-18 and IL-18BP when studying the role of IL-18 in diseases. Dengue has become one of the most important arboviral infections in the world (1). Dengue virus infection usually manifests as a self-limiting febrile illness. A subset of patients, however, develops life-threatening complications, which include plasma leakage, bleeding, and/or severe organ failure (2, 3). These complications usually occur during or shortly after defervescence in the so-called critical phase. The precise pathogenesis of these complications is not yet fully understood, but a massive secretion of cytokines by activated monocytes/macrophages and T lymphocytes is assumed to play a pivotal role (3-6).Interleukin-18 (IL-18) is a member of the IL-1 family of cytokines. It is synthesized as an inactive precursor requiring processing by caspase-1 into an active cytokine. The precursor is constitutively expressed by nearly all cells in humans. Dengue virus has been shown to activate the inflammasome and induce the production of IL-18 by human macrophages (7). IL-18, together with IL-12, plays a major role in the production of gamma interferon (IFN-␥). This was also shown in a murine dengue model, in which IL-18 acted in synergism with IL-12 to induce IFN-␥ and other T-helper 1 cytokines, which are considered central mediators in dengue host defense (8, 9).Previous studies in patients with acute dengue have reported high serum IL-18 levels, which correlated with disease severity (10-12). However, the activity of IL-18 is balanced by a natura...

show abstract

“…The fact that IL-18R␣ is constitutively expressed on some macrophages and can be upregulated, thus permitting direct induction of cytokine production by macrophages exposed to IL-18, also supports an autocrine pathway of IL-18-macrophage activation (32). IL-18BP gene expression was also upregulated in AN, consistent with the fact that IFN-␥ induces IL-18BP production (31).…”

Section: Discussionmentioning

confidence: 60%

Interleukin-18 binding protein therapy is protective in adriamycin nephropathy

Wyburn

Chadban

Kwan

et al. 2013

American Journal of Physiology-Renal Physiology

View full text Add to dashboard Cite

Adriamycin nephropathy (AN) is an experimental model of focal segmental glomerulosclerosis (FSGS) in which macrophages are considered to play a pathogenic role. We hypothesize that interleukin-18 (IL-18), largely derived from macrophages, is a key contributor to kidney injury in AN and a potential therapeutic target. In this study, BALB/c mice received adriamycin (9.6 mg/kg) via tail vein injection and subsequently were treated with either neutralizing IL-18 binding protein (IL-18BP; 250 μg) or normal saline (control). At 5 wk, IL-18 was upregulated in AN, and IL-18BP therapy afforded significant protection against the development of AN, resulting in less proteinuria ( P < 0.01), kidney dysfunction ( P < 0.01), glomerulosclerosis ( P < 0.001), and interstitial accumulation of macrophages and T cells ( P < 0.001). Gene expression of IL-18 downstream inflammatory molecules, including inducible nitric oxide synthase ( P < 0.001), TNF-α ( P < 0.001), and IFN-γ ( P < 0.01); IL-17 ( P < 0.001) and the chemokines CCL2 ( P < 0.01) and CCL5 ( P < 0.005), was reduced. We demonstrate that IL-18 plays a significant role in the pathogenesis of AN. The protective effect of IL-18BP therapy illustrates the importance of immune mediators in chronic proteinuric kidney disease and highlights the potential of IL-18BP therapy.

show abstract

Interferon-γ Mediates Gene Expression of IL-18 Binding Protein in Nonleukocytic Cells

Cited by 90 publications

References 30 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

Normal Free Interleukin-18 (IL-18) Plasma Levels in Dengue Virus Infection and the Need To Measure Both Total IL-18 and IL-18 Binding Protein Levels

Interleukin-18 binding protein therapy is protective in adriamycin nephropathy

Contact Info

Product

Resources

About