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Interleukin 10 (IL-10) Inhibition of Primary Human Prostate Cell-induced Angiogenesis

IL-10 Stimulation of Tissue Inhibitor of Metalloproteinase-1 and Inhibition of Matrix Metalloproteinase (MMP)-2/MMP-9 Secretion

Department of Pathology and Laboratory Sciences, Medical College of Pennsylvania and Hahnemann University, Philadelphia, Pennsylvania 19102-1192 [M. E. S., M. W.]; and National Cancer Institute, NIH, Bethesda, Maryland [J. R.]

In in vitro angiogenesis assays, aggregates of human papilloma virus (HPV)-18-immortalized primary human prostate cancer cells (HPCA-5aHPV-18 or HPCA-10aHPV-18 cells) induced human bone marrow endothelial cells (HBMCE-1 cells) to form microvessels in three-dimensional collagen I gels after 1–2 days incubation at 37°C. The microvessels aligned perpendicular to the tumor aggregates and abutted on the edges of the aggregates. The number and length of the microvessels increased significantly from day 1 to 2 (i.e., by 30%). ELISAs showed that the HPCA-5aHPV-18 cells normally secreted low levels of tissue inhibitor of metalloproteinase (TIMP)-2, matrix metalloproteinase (MMP)-2, and MMP-9 but relatively high levels of TIMP-1. In contrast, HPCA-10aHPV-18 cells secreted high levels of MMP-2 and MMP-9 (>40 pg/µg protein) but low levels of TIMP-1 and TIMP-2 (<5 pg/µg protein). Interleukin 10 (IL-10) (15 ng/ml) induced TIMP-1 production (>15 pg/µg protein) but reduced MMP-2 and MMP-9 secretion (<5 pg/µg protein) by the HPCA-5aHPV-18 and HPCA-10aHPV-18 cells. IL-10 (15 ng/ml) and MMP-9/MMP-2 antibodies all blocked induction of microvessel formation in the coculture experiments. In contrast, IL-10 receptor antibodies and TIMP-1 antibodies countered IL-10’s effects and promoted angiogenesis. The data demonstrated that IL-10 stimulation of TIMP-1 and inhibition of MMP-2 and MMP-9 secretion by prostate tumor cells can control induction of angiogenesis in vitro.

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