Cell lines derived from Kaposi sarcoma lesions of patients with AIDS (AIDS-KS cells) produce several cytokines, including an endothelial cell growth factor, interleukin lf, and basic fibroblast growth factor. Since exposure to human immunodeficiency virus increases interleukin 6 (IL-6) production in monocytes and endothelial cells produce IL-6, we examined IL-6 expression and response in AIDS-KS cell lines and IL-6 expression in AIDS Kaposi sarcoma tissue. The AIDS-KS cell lines (N521J and EKS3) secreted large amounts of immunoreactive and biologically active IL-6. We found both IL-6 and IL-6 receptor (IL-6-R) RNA by slot blot hybridization analysis of AIDS-KS cells. The IL-6-R was functional, as[3H]thymidine incorporation by AIDS-KS cells increased significantly after exposure to human recombinant IL-6 (hrIL-6) at >10 units/ml. When AIDS-KS cells (EKS3) were exposed to IL-6 antisense oligonucleotide, cellular proliferation decreased by nearly two-thirds, with a corresponding decrease in the production of IL-6. The decrease from IL-6 antisense in AIDS-KS cell proliferation was reversed by the addition of hrIL-6. We confimed that AIDS-KS cells produced IL-6 in vivo by preparing RNA and tissue sections from involved and uninvolved skin from a patient with AIDS Kaposi sarcoma. We detected immunoreactive IL-6 in the involved tumor areas and to a lesser extent in the surrounding normal epidermis. Slot blot hybridization showed a great excess of IL-6 and IL-6-R RNA in involved skin compared to uninvolved skin. These results show that both IL-6 and IL-6-R are produced by AIDS-KS cells and that IL-6 is required for optimal AIDS-KS cell proliferation, and they suggest that IL-6 is an autocrine growth factor for AIDS-KS cells.
Oncostatin M, a cytokine produced by activated lymphoid cells, regulates the growth and differentiation of a number of tumor and normal cells. In contrast to its effects on normal endothelial and aortic smooth muscle cell cultures, Oncostatin M was a potent mitogen for cells derived from acquired immunodeficiency syndrome-related Kaposi's sarcoma (AIDS-KS). After exposure to Oncostatin M, AIDS-KS cells assumed a spindle morphology, had an increased ability to proliferate in soft agar, and secreted increased amounts of interleukin-6. Oncostatin M RNA and immunoreactive Oncostatin M protein were found in AIDS-KS-derived cell isolates. These results suggest that Oncostatin M may play a role in the pathogenesis of AIDS-KS.
The cytotoxicity and antitumor effects of the acetogenin Bullatacin were evaluated in vitro in multiple ovarian cancer cell lines and in vivo in a murine ovarian teratocarcinoma (MOT) model in C3HeB/FeJ mice. The in vitro cytotoxicity of Bullatacin against four human ovarian epithelial tumor cell lines (OC-194, OC-222, OVCAR-3, and A-2780) was assessed in 48- and 72-h tetrazolium-dye (MTT) cytotoxicity assays. The percentage of cytotoxicity was determined on the basis of the mean optical density of the respective untreated cells and the dose effective against 50% of the cells (ED50) was calculated for each cell line. In vivo experiments were performed on adult female C3HeB/FeJ mice, which were injected i.p. with 10(5) MOT cells and varying amounts of Bullatacin given either in a single dose or in 5 subsequent doses over 72 h. All mice were observed for survival relative to that of the control groups, which were injected either with 10(5) MOT cells with or without serial injections of vehicle or with vehicle only. All four epithelial ovarian cancer cell lines displayed sensitivity to Bullatacin. The relative cytotoxic effects were very heterogeneous, with the ED50 value ranging between 10(-7) micrograms/ml for OC-194 and 4 micrograms/ml for the cisplatin-resistant cell line OVCAR-3 in a 72-h MTT cytotoxicity assay. All mice that had been injected i.p. with 10(5) MOT cells and 1.4 mg/kg or more of Bullatacin died within the first 24 h after injection, whereas all mice that had received 600 micrograms/kg of Bullatacin or less survived equally as long as the controls that had been injected with MOT only (21.1 +/- 0.9 days). Mice that had received Bullatacin at a dose ranging from 600 micrograms/kg to 1.4 mg/kg either died during the 1st day postinjection or survived, but not longer than the MOT control group. Serial i.p. injections of Bullatacin again either led to death of the mice within 24-48 h of the last dose of Bullatacin or did not have any effect on the survival of the mice as compared with the respective control groups, which had been injected with the tumor and serial injections of vehicle (22.5 +/- 2.2 days). In summary, Bullatacin showed no effect on MOT-caused animal death in C3HeB/FeJ mice at nonlethal dose ranges, whether it was given as a single i.p. dose or serially over 72 h. In vitro, however, it proved to be a very potent cytotoxic agent in a variety of ovarian cancer cell lines.(ABSTRACT TRUNCATED AT 400 WORDS)
The activity of both serum and effector cell antibody-dependent cellular cytotoxicity (ADCC) against human immunodeficiency virus (HIV-1, HIV) was assessed in HIV-infected individuals. The goal was to relate ADCC levels with the stage or progression of HIV disease. Serial serum samples, usually collected at 6-month intervals, from individuals at defined stages of HIV disease (seroconversion, the HIV-seropositive period before AIDS, and around the time of clinical AIDS diagnosis) were tested. HIV-coated CEM tumor cells were used as targets. Effector-cell ADCC activity was evaluated using fresh peripheral blood mononuclear cells (PBMC) from HIV-infected individuals at different stages of HIV disease. Samples were obtained from male homosexual participants in the Multicenter AIDS Cohort Study (MACS). In seroconverters, ADCC-inducing HIV-specific antibodies were detected at the time that the ELISA antibody test was first positive. Within several months, serum ADCC activity stabilized in each individual. In 29 HIV-seroprevalent individuals (HIV seropositive on their first visit), serum ADCC activity remained constant regardless of whether the individual's HIV disease was stable (high stable CD4; n = 9) or rapidly deteriorating (sharply declining CD4, n = 10; AIDS progressors, n = 10). With respect to effector-cell activity, PBMC from HIV-infected individuals with or without AIDS were capable of mediating ADCC with heterologous and usually with autologous sera. Although the level of NK cytotoxic activity and the level of antibody-armed effector cell activity have been reported to decline as disease progresses, our results support previous observations that ADCC effector-cell activity against antibody-coated targets does not decline in HIV infection.(ABSTRACT TRUNCATED AT 250 WORDS)
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