The role of endogenous interleukin-2 in proliferation of human carcinoma cell lines.
Interleukin (IL-2) and IL-2Rbeta/gamma have been shown to be expressed in human carcinomas in culture and in situ. Recently, expression of endogenous IL-2 and IL-2R in the cytoplasm was found to be up-regulated in tumour cells undergoing mitosis. This observation suggested that similar to its role in lymphocytes, the IL-2/IL-R pathway is involved in the regulation of carcinoma cell proliferation. Metabolic labelling followed by immunoprecipitation and Western blot results showed that IL-2 in carcinomas was identical to that in human lymphocytes. However, tumour cells did not secrete IL-2 detectable by immunoassays, although membrane-associated IL-2 was detectable on a proportion of these cells cultured in the absence of exogenous IL-2. Antibodies to IL-2 failed to inhibit proliferation of carcinoma cells, but antibodies specific for the ligand-binding site of the IL-2R were growth inhibitory. Growth of tumour cells was also inhibited by the immunosuppressive drugs, cyclosporin A (CsA), FK506 and rapamycin (RPA), known to interfere with the IL-2 pathway in lymphocytes. To further confirm the role of endogenous IL-2 in the growth of carcinomas, tumour cells were incubated with an IL-2-specific antisense oligonucleotide. The treatment was shown to transiently inhibit IL-2 mRNA and IL-2 protein expression as well as proliferation of tumour cells. Tumour cells treated with IL-2-specific antisense oligonucleotide demonstrated increased apoptosis in comparison to untreated or sense oligonucleotide-treated control cells. The data indicate that in human carcinomas, endogenous IL-2 promotes growth and protects tumour cells from apoptosis.
Reichert
T E
TE
University of Pittsburgh Cancer Institute, PA 15213, USA.
Kashii
Y
Y
Stanson
J
J
Zeevi
A
A
Whiteside
T L
TL
D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D002294:Carcinoma, Squamous Cell / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D006258:Head and Neck Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D019169:Jurkat Cells; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D015375:Receptors, Interleukin-2 / Q000276:immunology; D020123:Sirolimus / Q000494:pharmacology; D013274:Stomach Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016559:Tacrolimus / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000906:Antibodies; D007376:Interleukin-2; D016376:Oligonucleotides, Antisense; D015375:Receptors, Interleukin-2; D020123:Sirolimus; D016559:Tacrolimus