Modulation of interleukin-18 expression in human colon carcinoma: consequences for tumor immune surveillance.
The production in colon cancer of interferon-gamma (IFN-gamma), a type-1 T-helper (TH1) cytokine, is considered as a marker of good prognosis. We asked whether interleukin-18 (IL-18), which strongly induces IFN-gamma and regulates Fas ligand (Fas-L)-dependent cytotoxicity, may play a role in colon homeostasis, and if its expression was modulated in colon adenocarcinomas. We analyzed 14 specimens of colon adenocarcinomas, 6 of normal colon mucosa of the series, and 6 colon-tumor cell lines. The expression of IL-18, of ICE protease, involved in the processing of this cytokine, and of the downstream effectors of IL-18, IFN-gamma and Fas-L was analyzed by RT-PCR. We further performed IL-18 immunostaining of normal and tumor specimens. The results were correlated with tumor dissemination and clinical outcome. We report the synthesis of IL-18 in human normal colon, mainly by epithelial cells of the mucosa. Out of the 6 tumor cell lines, 4 expressed IL-18 transcripts, but neither ICE mRNA nor secreted forms of IL-18 were detected. We observed decreased or abolished synthesis of IL-18 in colon adenocarcinomas, as compared with normal mucosa. Thus, half of the colon-cancer tissues (7/14 cases) expressed neither IFN-gamma nor Fas-L. This feature was correlated with the existence of distant metastases (Fischer's exact test, p = 0.02) and an unfavorable outcome. These findings suggest that production of IL-18 in human colon may play a role in homeostasis and in tumor immune surveillance, by enhancing IFN-gamma production and Fas-L-dependent cytotoxicity of immune cells.
Pagès
F
F
Laboratoire d'Immunologie Cellulaire et Clinique, Unité INSERM U255, Institut Curie, Paris, France. franck.pages@curie.fr
Berger
A
A
Henglein
B
B
Piqueras
B
B
Danel
C
C
Zinzindohoue
F
F
Thiounn
N
N
Cugnenc
P H
PH
Fridman
W H
WH
D020170:Caspase 1 / Q000235:genetics; D003106:Colon / Q000378:metabolism; D003110:Colonic Neoplasms / Q000276:immunology*; D053222:Fas Ligand Protein; D006801:Humans; D007371:Interferon-gamma / Q000032:analysis; D020382:Interleukin-18 / Q000096:biosynthesis* / Q000235:genetics; D007413:Intestinal Mucosa / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis; D014407:Tumor Cells, Cultured
C505661:FASLG protein, human; D053222:Fas Ligand Protein; D020382:Interleukin-18; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D007371:Interferon-gamma; D020170:Caspase 1