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Expression in Human Peripheral Blood T Cells: Implications for Cancer Immunotherapy1
Department of Medicine and Stanley S. Scott Cancer Center, Louisiana State University Medical Center, New Orleans, LA 70112
Bryostatin-1 (Bryo-1), a protein kinase C modulator with
antineoplastic activity, may exert some of its antitumor activity
through activation of the immune response. Studies in tumor-bearing
hosts have indicated that the T cell response, particularly IFN-
production, is impaired. To evaluate whether Bryo-1 plus IL-2 may
affect the activation pattern of T cells, we investigated the
expression of IFN- mRNA and protein in human primary T cells.
Northern blot analysis and ELISAs demonstrated that Bryo-1 and IL-2
synergized to induce both IFN- mRNA and protein expression. This
synergistic induction was seen within 3 h of treatment and with as
little as 10 U/ml IL-2 and 1.0 ng/ml Bryo-1. In vitro transcription
assays revealed that Bryo-1 plus IL-2 induced transcriptional
activation of the IFN- gene. Furthermore, mRNA stability studies
indicated that this treatment also enhanced the IFN- mRNA half-life.
Both CD4+ and CD8+ T cells responded to the
treatment with IFN- expression. The induction of the IFN-
expression was decreased by a specific p38 mitogen-activated protein
kinase inhibitor, but not by a protein kinase C inhibitor. Our results
demonstrate for the first time that Bryo-1 in combination with IL-2
control IFN- gene expression at both the transcriptional and
post-transcriptional levels through a p38 mitogen-activated protein
kinase-dependent process. Given the pivotal role that IFN- plays in
the orchestration of an effective Th1 type of response, our results
suggest that Bryo-1 plus IL-2 may be a valuable combined therapy for
cancer treatment.
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