Cytokine regulation of the matrix metalloproteinases and their inhibitors in human papillomavirus-18 transformed human prostatic tumor cell lines.

Cytokines may play a critical role in influencing the invasive and metastatic behavior of advanced cancers. To investigate the influence of cytokines on tissue inhibitor of metalloproteinase (TIMP) and matrix metalloproteinase (MMP) expression we have established cultures from prostate tissues of low Gleason sum 5 and high Gleason sum 10 cancers. We have examined the influence of different cytokines (interleukin [IL]-10, IL-4, IL-6, IL-2, and interferon-gamma) on TIMP-2, MMP-2, and MMP-9 protein and mRNA expression in human papillomavirus (HPV)-18 immortalized human prostate cell lines derived from the primary cultures. Western blot and northern blot analysis revealed that IL-10, IL-6 and IL-4 all upregulated TIMP-1 expression after 16-36 h. In contrast, IL-10 and IL-4 (but not IL-6) downregulated MMP-2 mRNA and protein levels to different degrees over 24-36 h. The levels of TIMP-2 and MMP-9 protein and mRNA were not influenced substantially by any of the cytokines. Also, IL-2 and interferon-gamma had little or no effect on any of these genes. In sum, the data showed that IL-10 (or IL-4) upregulated TIMP-1 and coordinately downregulated MMP-2 expression. Thus, cytokines might control the molar ratio of TIMP-1 and MMP-2 to influence the level of protease activity and perhaps the invasive behavior of malignant cells in vivo.