IL-12 receptor-mediated upregulation of FasL in human ovarian carcinoma cells.
Abstact
The expression and functions of IL-12 receptor (IL-12R) in human ovarian carcinoma cell lines have been investigated. Ovarian carcinoma cells express both the IL-12Rbeta1 and the IL-12Rbeta2 subunits. IL-12R crosslinking resulted in phosphorylation of Tyk2, p44 (ERK1) and Akt kinases and activation of STATs 2, 3, 4 and 5. IL-12 induced substantial upregulation of Fas ligand (FasL) surface expression in ovarian carcinoma cells paralleled by an increased ability to induce apoptosis in Jurkat cells and PHA-activated lymphocytes. The induction of surface expression of FasL by IL-12 was not due to upregulation of FasL gene expression, but resulted from downregulation of matrix metalloproteinases (MMPs)-3 and -7 and consequently reduced cleavage of FasL from the cell surface. These findings bring new insights into the significance of IL-12-mediated effects in nonlymphoid cancer cells that might be of importance for improving the design of IL-12-based therapies for ovarian cancer.
Authors
- Drenning SD
- Edwards RP
- Feng X
- Gorelik E
- Grandis JR
- Kwon JA
- Lokshin AE
- Marrangoni AM
- Velikokhatnaya L