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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-gamma 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-gamma 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-gamma 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-gamma gene. Furthermore, mRNA stability studies indicated that this treatment also enhanced the IFN-gamma mRNA half-life. Both CD4(+) and CD8(+) T cells responded to the treatment with IFN-gamma expression. The induction of the IFN-gamma 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-gamma 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-gamma 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.

Bryostatin-1 and IL-2 Synergize to Induce IFN-γ Expression in Human Peripheral Blood T Cells: Implications for Cancer Immunotherapy