Bryostatin-1 and IL-2 synergize to induce IFN-gamma expression in human peripheral blood T cells: implications for cancer immunotherapy.
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.
Curiel
R E
RE
Department of Medicine and Stanley S. Scott Cancer Center, Louisiana State University Medical Center, New Orleans, LA 70112, USA.
Garcia
C S
CS
Farooq
L
L
Aguero
M F
MF
Espinoza-Delgado
I
I
D054713:Bryostatins; D003513:Cycloheximide / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D004357:Drug Synergism; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000235:genetics; D018793:Interleukin-13 / Q000096:biosynthesis; D007376:Interleukin-2 / Q000008:administration & dosage / Q000494:pharmacology*; D015847:Interleukin-4 / Q000096:biosynthesis; D007783:Lactones / Q000008:administration & dosage / Q000494:pharmacology*; D018942:Macrolides; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
D054713:Bryostatins; D018793:Interleukin-13; D007376:Interleukin-2; D007783:Lactones; D018942:Macrolides; D012333:RNA, Messenger; D015847:Interleukin-4; C046785:bryostatin 1; D003907:Dexamethasone; D007371:Interferon-gamma; D003513:Cycloheximide; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases