Activation of the interleukin-32 pro-inflammatory pathway in response to human papillomavirus infection and over-expressionof interleukin-32 controls the expression of the humanpapillomavirus oncogene

作者：Lee Sojung; Kim Jung Hee; Kim Heejong; Kang Jeong Woo; Kim Soo Hyun; Yang Young; Kim Jinman; Park JongSup; Park SurNie; Hong JinTae; Yoon Do Young^*

来源：Immunology, 2011, 132(3): 410-420.

DOI：10.1111/j.1365-2567.2010.03377.x

• cervical cancer
• cyclo-oxygenase-2
• feedback inhibition
• human papillomavirus E7
• interleukin-32

P>High-risk variants of human papillomavirus (HPV) induce cervical cancer by persistent infection, and are regarded as the principal aetiological factor in this malignancy. The pro-inflammatory cytokine interleukin-32 (IL-32) is present at substantial levels in cervical cancer tissues and in HPV-positive cervical cancer cells. In this study, we identified the mechanism by which the high-risk HPV-16 E7 oncogene induces IL-32 expression in cervical cancer cells. We used antisense transfection, over-expression, or knock-down of IL-32 to assess the effects of the HPV-16 E7 oncogene on IL-32 expression in cervical cancer cells. Cyclo-oxygenase 2 (COX-2) inhibitor treatment was conducted, and the expression levels, as well as the promoter activities, of IL-32 and COX-2 were evaluated in human HPV-positive cervical cancer cell lines. E7 antisense treatment reduced the expression levels and promoter activities of COX-2, which is constitutively expressed in HPV-infected cells. Constitutively expressed IL-32 was also inhibited by E7 antisense treatment. Moreover, IL-32 expression was blocked by the application of the selective COX-2 inhibitor, NS398, whereas COX-2 over-expression resulted in increased IL-32 levels. These results show that the high-risk variant of HPV induces IL-32 expression via E7-mediated COX-2 stimulation. However, E7 and COX-2 were down-regulated in the IL-32 gamma over-expressing cells and recovered by IL-32 small interfering RNA, indicating that E7 and COX-2 were feedback-inhibited by IL-32 gamma in cervical cancer cells.

• 出版日期2011-3