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Molecular mechanisms underlying IFN-{gamma}-mediated tumor growth inhibition induced during tumor growth inhibition induced during tumor immunotherapy with rIL-12
Authors:Yu, Wen-Gong   Yamamoto, Noriniko   Takenaka, Hiroshi   Mu, Jie   Tai, Xu-Guang   Zou, Jian-Ping   Ogowa, Makoto   Tsutsui, Tateki   Wijesuriya, Rishani   Yoshida, Ryotaro   Herrmann, Steven   Fujiwara, Hiromi   Hamaoka, Toshiyuki
Affiliation:Biomedical Research Center,Osaka University Medical School,2-2 Yamada-oka,Suita,Osaka 565,Japan
1 Osaka Bioscience Institue Suita, Osaka 565, Japan
2 Genetics Institue Cambridge,MA 02140,USA
Abstract:The present studnt Investigates the molecular by which IFN-{gamma}produced as a result of in vitroIL-12 addministration exertsits anty-tumor,rIL-12 was administered three or five times intomice bearing CDA1M fibrosarcoma, OV-HM ovarian carcinoma orMCH-1-A1 fibosarcoma. This regimen induced complete regressionof CSA1M and OV-HM tumors but only transient growth inhibitionof MCH-1-A1 tumors. The anty-tumor effects of Il-12 were associatatedwith enhanced induction of IFN-{gamma}becouse these effects were abrogatedby pretreatment of hosts with anti-IFN-{gamma} antibody.Exposure inin vitro of the three types of tumor cells to rIFN-{gamma} resultedin moderate to potent inhibition of tumor cell growth.IFN{gamma}stimulatedthe expression of mRNAs for an inducible type of NO synthasa(INOS)in CSA1M cells and indoleamine 2,3-dioxygenasa (IDO),an enzyme capable of degrading tryptophan, in OV-HM cells ,but induced only marginal levels of these mRNAs in MCH-I-ALcells. In association withiNOS gene expression, INF-{gamma}-stimulatedCSA1M cells produced a large amount of NO which functioned toinhibit their own growth in vitro. Although OV-HM and MCH-1-A1cells did not produce NO, they also exhibited NO susceptibility.Whereasthe tumor masses from IL-12-treated CSA1M-bearing mice inducedhigher levels of INOS (for CSA1M) or IDO and iNOS (for OV-HM)mRNAs,the MCH-1-A1 tumor mass expressed lower levels of iNOS mRNAalone.Moreover, massive infiltration of CD4+and CD8+ T cellsand Mac-1+ cells was seen only in the CSA1M and OV-HM tumors.Thus, these results indicate that IFN-{gamma} produced after IL-12treatment induces the expression of various genes with potentialto modulate tumor cells and growth by acting directly on tumorecells or stimulating tumor-infiltrating lymphold cells and thatthe effectiveness of IL12 therapy is assoiated with the operation if these mechanisms.
Keywords:IFN-  /math/gamma.gif"   ALT="  {gamma}"   BORDER="  0"  >   IL-12   inducibel No synthase   turmor immunity
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