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IFN- and T-bet Expression in Human Dendritic Cells from Normal Donors and Cancer Patients Is Controlled through Mechanisms Involving ERK-1/2-Dependent and IL-12-Independent Pathways

Section of Hematology-Oncology, Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224

Dendritic cells (DC) play a major role in priming naive T cells and modulating the immune response. We have previously reported that bryostatin-1, a potent immune modulator with antitumor activity, activates monocytes and lymphocytes to produce cytokines. Studies have shown that tumor-bearing hosts have a Th1/Th2 cytokine pattern that is associated with decreased production of IFN-. We investigated the expression of IFN- in bryostatin-1-treated human DC. Bryostatin-1 induced both IFN- and T-bet mRNA expression in a dose- and time-dependent manner. As little as 1 ng/ml bryostatin-1 induced IFN- and T-bet transcripts within 3 h and protein at 12 h. Treatment of DC with cycloheximide revealed that bryostatin-1-induced T-bet expression requires de novo protein synthesis, but bryostatin-1-induced IFN- expression is independent of protein synthesis. Furthermore, dexamethasone inhibits bryostatin-1-induced IFN- mRNA expression but increases bryostatin-1-induced T-bet mRNA expression. Experiments with ERK-1/2 inhibitors demonstrated that bryostatin-1 induction of IFN- and T-bet was ERK-dependent and IL-12-independent. Similar results were obtained from both normal donors and cancer patients. In summary, our results suggest that bryostatin-1-induced IFN- expression is T-bet independent. They also suggest for the first time that IFN- and T-bet can be induced in human DC through an ERK-dependent pathway. Bryostatin-1-induced IFN- may play a crucial role in the initiation of the immune response, before specific recognition by T cells that could be beneficial in the treatment of cancer.

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¹ Address correspondence and reprint requests to Dr. Igor Espinoza-Delgado, 5600 Nathan Shock Drive, Room 4C10, Baltimore, MD 21224. E-mail address: espinozaig{at}grc.nia.nih.gov

² Abbreviations used in this paper: PKC, protein kinase C; DC, dendritic cell; LGL, large granular lymphocyte; CHX, cycloheximide; DEX, dexamethasone; BI, bisindolylmaleimide I; BDCA, blood DC Ag; iDC, immature DC; mDC, mature DC; RT-qPCR, real-time quantitative PCR.