IL-12 receptor-mediated upregulation of FasL in human ovarian carcinoma cells.
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.
Gorelik
Elieser
E
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Edwards
Robert P
RP
Feng
Xin
X
Marrangoni
Adele M
AM
Grandis
Jennifer R
JR
Drenning
Stephanie D
SD
Velikokhatnaya
Lyudmila
L
Kwon
Jeong-Ah
JA
Lokshin
Anna E
AE
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000954:Antigens, Surface; D017209:Apoptosis; D002277:Carcinoma / Q000473:pathology*; D053222:Fas Ligand Protein; D005260:Female; D006801:Humans; D018664:Interleukin-12 / Q000494:pharmacology*; D008024:Ligands; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D010051:Ovarian Neoplasms / Q000473:pathology*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D019014:fas Receptor
D020533:Angiogenesis Inhibitors; D000954:Antigens, Surface; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008024:Ligands; D008562:Membrane Glycoproteins; D019014:fas Receptor; D018664:Interleukin-12