Exploitation of interleukin-18 by gastric cancers for their growth and evasion of host immunity.
Interleukin-18 (IL-18) is a pleiotropic cytokine that enhances Th1 or Th2 immune response. We show a novel mechanism of gastric cancer cells that allows their immune escape utilizing IL-18. All 4 gastric cancer cell lines, but not colon lines, constitutively expressed IL-18 receptors and IL-18 dose-dependently enhanced their in vitro proliferation accompanied by nuclear factor kappaB activation. When IL-18-pretreated gastric cancer cells were cultured with cytokine-activated peripheral blood killer lymphocytes, the antitumor machineries, perforin or interferon-gamma production of killer lymphocytes decreased, resulting in a decreased susceptibility of cancer cells to killer lymphocytes. Furthermore, gastric cancer cells cultured with IL-18 showed an increased expression of a granzyme B inhibitor, protease inhibitor 9. IL-18 injections into severe combined immuno-deficient mice intraperitoneally inoculated with gastric cancer cells consistently decreased the mouse survival time. Our results indicate that gastric cancers exploit IL-18 to grow/invade and evade immunosurveillance in the hosts.
Majima
Takashi
T
Department of Surgery I, National Defense Medical College, Tokorozawa, Japan. majima@ndmc.ac.jp
Ichikura
Takashi
T
Chochi
Kentaro
K
Kawabata
Toshinobu
T
Tsujimoto
Hironori
H
Sugasawa
Hidekazu
H
Kuranaga
Noritsugu
N
Takayama
Eiji
E
Kinoshita
Manabu
M
Hiraide
Hoshio
H
Seki
Shuhji
S
Mochizuki
Hidetaka
H
D000818:Animals; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000276:immunology; D018450:Disease Progression; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D020382:Interleukin-18 / Q000276:immunology*; D051379:Mice; D016513:Mice, SCID; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015843:Serpins / Q000096:biosynthesis; D013274:Stomach Neoplasms / Q000276:immunology* / Q000473:pathology*; D016019:Survival Analysis; D014407:Tumor Cells, Cultured; D019139:Tumor Escape / Q000276:immunology*
D020382:Interleukin-18; C102316:SERPINB9 protein, human; D015843:Serpins