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Expression of inducible nitric oxide synthase in tumors in relation with their regression induced by lipid A in rats
N Onier1, S Hilpert, S Reveneau
1Laboratoire d'Immunologie et d'Immunothérapie des Cancers, Ecole Pratique des Hautes Etudes, INSERM U517, Université de Bourgogne, Dijon, France.
Abstract:
It is well documented that nitric oxide (NO) is an effector molecule of macrophage-mediated tumor cell toxicity in vitro; however, little is known about the role of NO in the antitumor immune response in vivo. We have developed a treatment protocol using lipid A. We have investigated the effects of lipid A on inducible NO synthase (NOS II) expression and evolution inside tumors during the course of treatment. Lipid A (OM-174) treatment induced tumor regression in rats bearing established colon tumors. Furthermore, NO was synthesized and secreted inside the tumors of lipid A-treated rats, as demonstrated by the increase of NOS II mRNA and NOS II content in the tumors, as well as of NOS II activity and NO production. During treatment, NOS II was localized in tumor cells only. Lipid A had no direct effect on tumor cells in vitro, while the combination of interferon gamma (IFN-gamma) plus interleukin-1 beta (IL-1beta) induced production of NO by tumor cells which was cytostatic. The content of IFN-gamma and IL-1beta in tumors was enhanced during lipid A treatment; this is in agreement with an indirect effect of lipid A in vivo via the IFN-gamma and IL-1beta pathways.
Insights
Lipid A treatment promotes tumor regression by inducing nitric oxide (NO) synthesis within tumors. This occurs indirectly via enhanced interferon gamma and interleukin-1 beta, highlighting NO
Area of Science:
- Immunology
- Oncology
- Biochemistry
Background:
- Nitric oxide (NO) is a known mediator of macrophage-dependent tumor cell toxicity in vitro.
- The role of NO in in vivo antitumor immune responses remains less understood.
Purpose of the Study:
- To investigate the effects of lipid A on inducible NO synthase (NOS II) expression and NO production within tumors during treatment.
- To elucidate the mechanism of lipid A-mediated tumor regression in vivo.
Main Methods:
- Treatment of rats with colon tumors using lipid A (OM-174).
- Analysis of NOS II mRNA, NOS II protein content, NOS II activity, and NO production in tumors.
- In vitro studies on the direct effects of lipid A on tumor cells and cytokine-induced NO production.
Main Results:
- Lipid A treatment led to significant tumor regression in rats.
- Increased NOS II mRNA, NOS II content, NOS II activity, and NO production were observed within tumors following lipid A administration.
- NOS II was localized specifically in tumor cells during treatment.
- Lipid A enhanced the content of interferon gamma (IFN-gamma) and interleukin-1 beta (IL-1beta) in tumors, suggesting an indirect mechanism.
Conclusions:
- Lipid A effectively induces tumor regression in vivo.
- The antitumor effect is mediated by NO synthesized within tumors, upregulated through NOS II expression.
- Lipid A appears to act indirectly by increasing tumor levels of IFN-gamma and IL-1beta, which in turn stimulate NO production by tumor cells.
