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

Abstract

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.

Regulation of interleukin‐18 binding protein production by blood and synovial cells from patients with rheumatoid arthritis

“…Healthy or RA PBMCs constitutively produced significant levels of IL-18BP. The increased expression and release of IL-18BP in response to IFN␥ has been reported (15). However, the addition of IL-12 decreased IL-18BP production from PBMCs in spite of increasing IFN␥ production in the same culture.…”

Adenoviral delivery of IL-18 binding protein C ameliorates Collagen-Induced Arthritis in mice

“…Elevated levels of IL-18BP are found in serum of patients suffering from septic shock and IL-18BP is expressed in response to IFNg. 13 Several isoforms have been discovered resulting from alternative mRNA splicing of which IL-18BPa and IL-18BPc exhibit the highest affinity towards IL-18. 14 These isoforms are able to neutralize 495% of the biological activity of IL-18 at a 1:1 molar ratio.…”

Interleukin-18 directly activates T-bet expression and function via p38 mitogen-activated protein kinase and nuclear factor-κB in acute myeloid leukemia–derived predendritic KG-1 cells

“…Besides T cells and natural killer cells, human dendritic cells (DC) are also capable of potently releasing IFNg under the influence of IL-18 (3,10). IL-18 biological activity seems to be controlled by an IFNginduced negative feedback loop mediated by the IL-18 opponent IL-18 -binding protein (11). Interestingly, it has recently been shown that IL-18 was able to induce the maturation of human monocyte -derived dendritic cells with regard to biochemical as well as functional characteristics (12).…”