The relationship between the antitumor effect of the IL-12 gene therapy and the expression of Th1 cytokines in an HPV16-positive murine tumor model.

Flor García Paz,Eva Hernandez Marquez,Kirvis Torres Poveda,Oscar Peralta Zaragoza,Abimelec Santander González,Vicente Madrid Marina,Ausencio Morales Ortega,Juan Alcocer González,Ana Burguete García,Victor Bermúdez Morales,José Moreno

doi:10.1155/2014/510846

Flor García Paz, Eva Hernandez Marquez + Show 9 more

Open Access

https://doi.org/10.1155/2014/510846

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Abstract

Objective. The goal of the present study was to investigate the effect of IL-12 expressed in plasmid on the Th1 cytokine profile in an experimental HPV16-positive murine tumor model and the association with the IL-12's antitumor effect. Methods. Mice were injected with BMK-16/myc cells to establish HPV16-positive tumor and then pNGVL3-mIL-12 plasmid; pcDNA3 plasmid or PBS was injected directly into tumor site. The antitumor effect of the treatment was evaluated and the cytokines expression profile in each tumor tissue was analyzed. Results. Treatment with pNGVL3-mIL-12 plasmid had a significant antitumor effect, and a Th2-Th3-type cytokines prolife was detected in the murine tumor model with expression of the cytokines IL-10, IL-4, and TGF-β1. However, after the tumor was treated with three intratumoral injections of plasmid containing IL-12 cDNA, it showed a cytokine profile associated with Th1 with expression of IL-2, IL-12, and IFN-γ cytokines and reduced expression of IL-10, IL-4, and TGF-β1. Conclusions. The treatment with the IL-12 gene in the experimental HPV16-positive tumor model promoted the activation of the cellular immune response via expression of a Th1-type cytokine profile and was associated with the inhibition of tumor growth. Thus, IL-12 treatment represents a novel approach for gene therapy against cervical cancer.

Highlights

Cervical cancer continues to be a serious public health problem worldwide and there is much room for improvement in the prevention, control, and treatment of this neoplasia
After the tumor was treated with three intratumoral injections of plasmid containing IL-12 cDNA, it showed a cytokine profile associated with Th1 with expression of IL-2, IL-12, and IFN-γ cytokines and reduced expression of IL-10, IL-4, and TGF-β1
The results are shown in Figure 1: inhibition of tumor growth was clearly observed in the mice treated with the pNGVL3-murine IL-12 gene expression (mIL-12) plasmid for at least 15 days, P < 0.05

Summary

Introduction

Cervical cancer continues to be a serious public health problem worldwide and there is much room for improvement in the prevention, control, and treatment of this neoplasia. There is substantial evidence that cervical cancer is associated with HPV infection, and that anti-inflammatory and immunosuppressive cytokines are expressed in the cervical microenvironment, determining the persistence of HPV: in this scenario a local immunosuppressive state could accelerate cellular proliferation and tumor growth. The balance of expression of Th1/Th2/Th3-type cytokines such as IL-4, IL10, and TGF-β1 in the cervical mucosa, cervical mucus [9], and tumor cells during HPV infection influences the immune status in the local cervical microenvironment and determines the persistence of HPV, progression of dysplasia into invasive cancer, and cervical cancer progression [4,5,6]

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