IFN-gamma 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.
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-gamma. We investigated the expression of IFN-gamma in bryostatin-1-treated human DC. Bryostatin-1 induced both IFN-gamma and T-bet mRNA expression in a dose- and time-dependent manner. As little as 1 ng/ml bryostatin-1 induced IFN-gamma 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-gamma expression is independent of protein synthesis. Furthermore, dexamethasone inhibits bryostatin-1-induced IFN-gamma mRNA expression but increases bryostatin-1-induced T-bet mRNA expression. Experiments with ERK-1/2 inhibitors demonstrated that bryostatin-1 induction of IFN- gamma 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-gamma expression is T-bet independent. They also suggest for the first time that IFN- gamma and T-bet can be induced in human DC through an ERK-dependent pathway. Bryostatin-1-induced IFN- gamma 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.
Li
Huifen
H
Section of Hematology-Oncology, Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
Wojciechowski
Wojciech
W
Dell'Agnola
Chiara
C
Lopez
Natalia E
NE
Espinoza-Delgado
Igor
I
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D054713:Bryostatins; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000235:genetics; D018664:Interleukin-12 / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology*; D018942:Macrolides / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000502:physiology*; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology*; D012333:RNA, Messenger / Q000096:biosynthesis; D020825:T-Box Domain Proteins; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D000098815:T-bet Transcription Factor
D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D054713:Bryostatins; D018942:Macrolides; D012333:RNA, Messenger; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014157:Transcription Factors; D018664:Interleukin-12; C046785:bryostatin 1; D007371:Interferon-gamma; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3