IL-18 is produced by prostate cancer cells and secreted in response to interferons.
Murine models have shown that IL-18 has antiangiogenic and antitumor effects, but little is known about IL-18 production in human tumors. We investigated IL-18 expression in clinically localized prostate cancers by immunohistochemistry and showed that 75% of the prostate cancers studied (27/36 cases) presented with tumor cells producing IL-18. Prostate tumor cell lines PC-3, DU 145 and LNCaP synthesized the immature form of IL-18 (p24). IFN-gamma produced in prostate cancers induced caspase-1 mRNA and IL-18 secretion of tumor cell lines, which was inhibited by the cell-permeable Tyr-Val-Ala-Asp-aldehyde caspase-1 inhibitor (YVAD-CHO). Interestingly, IFN-alpha also induced IL-18 secretion of the poorly differentiated cell line PC-3. PC-3 and DU 145, but not the well-differentiated cell line LNCaP, expressed IL-18R alpha (IL-1Rrp) protein and transcripts for IL-18R beta (AcPL). Exogenous IL-18 increased mitochondrial activity of both cell lines evaluated by the tetrazolium (MTT) assay but did not influence their proliferation. This indicated that prostate tumor cells could secrete IL-18 in response to IFN-gamma in the tumor microenvironment and that IL-18 could act as a autocrine/paracrine factor for the tumor. In the cohort of patients studied, IL-18 expression in prostate cancers (with up to 10% of tumor cells stained) was associated with a favorable outcome and equally predictive as pathologic stage on multivariate analysis (log rank test, p = 0.02). Tumor IL-18 production is a novel physiopathologic feature of prostate cancer and appears to be a favorable event in the course of the disease. Modulation of IL-18 production by interferons could have a beneficial clinical effect, which deserves further investigation.
Lebel-Binay
Sophie
S
INSERM U 255, Centre de Recherches Biomédicales des Cordeliers, Paris, France.
Thiounn
Nicolas
N
De Pinieux
Gonzague
G
Vieillefond
Annick
A
Debré
Bernard
B
Bonnefoy
Jean-Yves
JY
Fridman
Wolf-Herman
WH
Pagès
Franck
F
D000970:Antineoplastic Agents / Q000494:pharmacology*; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism; D061945:Caspase Inhibitors; D002455:Cell Division / Q000187:drug effects; D015331:Cohort Studies; D017931:DNA Primers / Q000737:chemistry; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D016898:Interferon-alpha / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology*; D020382:Interleukin-18 / Q000096:biosynthesis*; D053727:Interleukin-18 Receptor alpha Subunit; D008297:Male; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D018123:Receptors, Interleukin / Q000378:metabolism; D053724:Receptors, Interleukin-18; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013778:Tetrazolium Salts; D013844:Thiazoles; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D061945:Caspase Inhibitors; D017931:DNA Primers; C508572:IL18R1 protein, human; D016898:Interferon-alpha; D020382:Interleukin-18; D053727:Interleukin-18 Receptor alpha Subunit; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053724:Receptors, Interleukin-18; D013778:Tetrazolium Salts; D013844:Thiazoles; D007371:Interferon-gamma; D017430:Prostate-Specific Antigen; D020170:Caspase 1; C022616:thiazolyl blue