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Mechanisms of Growth Control of Kaposi's Sarcoma-Associated Herpes
Virus-Associated Primary Effusion Lymphoma Cells
Hiroya Asou,
Jonathan W. Said,
Rong Yang,
Reinhold Munker,
Dorothy
J. Park,
Nanao Kamada, and
H. Phillip Koeffler
From the Division of Hematology/Oncology and Pathology, Cedars-Sinai
Medical Center, UCLA School of Medicine, Los Angeles, CA; and the
Department of Cancer Cytogenetics, Division of Molecular Biology,
Research Institute for Radiation Biology and Medicine, Hiroshima
University, Hiroshima, Japan.
Primary effusion lymphoma (PEL) is a distinct clinicopathologic
entity associated with Kaposi's sarcoma-associated herpes virus
(KSHV). Several cytokines, including interleukin-6 (IL-6), basic
fibroblast growth factor (bFGF), and platelet-derived growth factor
(PDGF) may be important for survival of KS cells. However, little is
known about the interaction of cytokines with KSHV-infected lymphocytes
from PEL. Therefore, we investigated what cytokines were produced by
KSHV-infected PEL cell lines (KS-1, BC-1, BC-2), what cytokine
receptors were expressed by these cells, what response these cells had
to selected cytokines, and what was the effect of IL-6 antisense
phosphorothioated oligonucleotides. Reverse transcriptase-polymerase
chain reaction (RT-PCR) and protein studies showed that these three
cell lines produced IL-10, IL-6, and the receptors for IL-6. The
granulocyte macrophage colony-stimulating factor (GM-CSF), IL-1 ,
IL-8, IL-12, bFGF, PDGF, and c-kit transcripts were not
detected in the cell lines. High levels (0.7 to 5 ng/mL/106
cells/48 hours) of IL-6 protein were consistently detected in supernatants of the cell lines by enzyme-linked immunosorbent assay
(ELISA) tests. In clonogenic assays, interferon- (IFN-) and
IFN- suppressed the clonal growth of the PEL cells, but GM-CSF, IL-4, IL-6, IL-8, IL-10, and oncostatin M did not change it. We examined for several autocrine loops that have been suggested to occur
in KS. Experiments using antisense oligonucleotides showed that the
clonal growth of KS-1 and BC-1 was nearly 100% inhibited by IL-6
antisense oligonucleotides (10 µmol/L), but not at all by either
oligonucleotides ( 10 µmol/L) to IL-6 sense, IL-6 scrambled, viral
IL-6 (vIL-6) antisense, or IL-10 antisense. Furthermore, the IL-6
antisense oligonucleotides had no effect on two B-cell lymphoma cell
lines, which were not infected with KSHV. Addition of IL-6 antibody did
not inhibit clonal growth of any of the cell lines. Taken together, we
have defined the cytokines and their receptors expressed on PEL cells
and have found that these cells synthesized IL-6 and IL-6 receptors;
interruption of this pathway by IL-6 antisense oligonucleotides
specifically prevented the growth of these cells. These findings will
offer potential new therapeutic strategies for PEL.
Blood, Vol. 91 No. 7 (April 1), 1998:
pp. 2475-2481
© 1998 by The American Society of Hematology.
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