Involvement of interleukin 18 in Crohn's disease: evidence from in vitro analysis of human gut inflammatory cells and from experimental colitis models.
An imbalance of immunoregulatory factors and/or cells contributes to uncontrolled mucosal T cell activation and inflammation in Crohn's disease (CD). Bioactive interleukin (IL)-18 has been shown to be produced by macrophages in CD lesions. We report here that T cells freshly isolated from inflamed tissue of CD patients (and not T cells from control intestinal tissue) were responsive to IL-18. In the presence of IL-18, these T cells produced more interferon (IFN)-gamma and less IL-10. To analyse further the role of IL-18 in this disease, an acute and a chronic model of murine colitis were used. IL-18 mRNA was significantly enhanced in trinitrobenzene sulphonic acid (TNBS) induced colitis, and treatment with IL-18 binding protein (IL-18BPa), which neutralizes IL-18 bioactivity, significantly reduced the severity of colitis. However, IL-18BPa did not affect the course of chronic colitis in CD45RBhighCD4+ T cell reconstituted SCID mice. Production of IFN-gamma in lamina propria mononuclear cell cultures from IL-18BPa-treated SCID mice was decreased, but at the same time fewer lamina propria CD4+ T cells harvested from IL-18BPa-treated mice compared to non-treated mice were in apoptosis. We conclude that IL-18 clearly has a modulatory role in the inflammatory cascade of CD and experimental colitis by affecting IFN-gamma and IL-10 production, and apoptosis. In view of the divergent effects of IL-18 neutralization in the two different murine colitis models, it is unlikely that IL-18 is at the top of this cascade.
Maerten
P
P
Laboratory of Experimental Immunology, University Hospital of Leuven, Belgium.
Shen
C
C
Colpaert
S
S
Liu
Z
Z
Bullens
D A M
DA
van Assche
G
G
Penninckx
F
F
Geboes
K
K
Vanham
G
G
Rutgeerts
P
P
Ceuppens
J L
JL
D000328:Adult; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D002908:Chronic Disease; D003092:Colitis / Q000276:immunology; D003424:Crohn Disease / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D006023:Glycoproteins / Q000276:immunology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D020382:Interleukin-18 / Q000276:immunology*; D015847:Interleukin-4 / Q000096:biosynthesis; D007413:Intestinal Mucosa / Q000276:immunology; D017493:Leukocyte Common Antigens / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009092:Mucous Membrane / Q000276:immunology; D016133:Polymerase Chain Reaction / Q000379:methods; D012333:RNA, Messenger / Q000032:analysis; D013601:T-Lymphocytes / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C118370:interleukin-18 binding protein; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma; D017493:Leukocyte Common Antigens