Expression and release of IL-18 binding protein in response to IFN-gamma.
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-gamma 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-gamma by IL-12/IL-18-stimulated PBMC. Inducibility of IL-18BPa by IFN-gamma 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-gamma-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-gamma 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.
Paulukat
J
J
Pharmazentrum Frankfurt and Second Department of Medicine, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany.
Bosmann
M
M
Nold
M
M
Garkisch
S
S
Kämpfer
H
H
Frank
S
S
Raedle
J
J
Zeuzem
S
S
Pfeilschifter
J
J
Mühl
H
H
D002087:Butyrates / Q000494:pharmacology; D018938:Caco-2 Cells; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism*; D006023:Glycoproteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007371:Interferon-gamma / Q000494:pharmacology*; D018664:Interleukin-12 / Q000494:pharmacology; D020382:Interleukin-18 / Q000494:pharmacology; D058610:Isobutyrates; D015603:Keratinocytes / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D009924:Organ Culture Techniques; D012333:RNA, Messenger / Q000096:biosynthesis; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
D002087:Butyrates; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18; D058610:Isobutyrates; D012333:RNA, Messenger; C118370:interleukin-18 binding protein; D018664:Interleukin-12; D007371:Interferon-gamma; C020380:isobutyric acid