The antineoplastic agent bryostatin-1 induces proinflammatory cytokine production in human monocytes: synergy with interleukin-2 and modulation of interleukin-2Rgamma chain expression.
The antineoplastic agent bryostatin-1 (bryo-1) possesses powerful immunomodulatory properties and can function as a biological response modifier in vivo. However, there is currently little information regarding the effects of bryo-1 on cells of the monocytic lineage. In this study, we demonstrate that bryo-1 can potently induce the production of pro-inflammatory cytokines from human peripheral blood monocytes. Stimulation of monocytes with subnanomolar concentrations of bryo-1 significantly upregulated the constitutive levels of interleukin-8 (IL-8) mRNA and induced the expression of IL-1beta, tumor necrosis factor-alpha (TNF-alpha), and IL-6 mRNA in a time and dose-dependent manner. Accordingly, secretion of all four proinflammatory cytokines was induced after monocyte exposure to bryo-1. Furthermore, we showed that bryo-1 selectively synergized with IL-2 in triggering monocyte activation, and this effect seemed to be dependent, at least in part, on the ability of bryo-1 to upregulate IL-2Rgamma chain expression. Finally, we demonstrated that the responses of monocytes to bryo-1 could be blocked by the protein kinase C (PKC) inhibitors staurosporine and UCN-01, indicating a role for PKC in monocyte activation by bryo-1. These results show for the first time that bryo-1 is a powerful activator of human monocytes and suggest that stimulation of monokine secretion by bryo-1 may represent at least one of the mechanisms responsible for the in vivo antitumor activity of this drug.
Bosco
M C
MC
Intramural Research Support Program, SAIC Frederick, MD, USA.
Rottschafer
S
S
Taylor
L S
LS
Ortaldo
J R
JR
Longo
D L
DL
Espinoza-Delgado
I
I
D000970:Antineoplastic Agents / Q000494:pharmacology*; D054713:Bryostatins; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D004357:Drug Synergism; D006801:Humans; D007249:Inflammation; D007375:Interleukin-1 / Q000096:biosynthesis; D007376:Interleukin-2 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D007700:Kinetics; D007783:Lactones / Q000494:pharmacology*; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology*; D018942:Macrolides; D046911:Macromolecular Substances; D009000:Monocytes / Q000187:drug effects / Q000276:immunology*; D012333:RNA, Messenger / Q000096:biosynthesis; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis*; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000970:Antineoplastic Agents; D054713:Bryostatins; D016207:Cytokines; D007375:Interleukin-1; D007376:Interleukin-2; D015850:Interleukin-6; D016209:Interleukin-8; D007783:Lactones; D018942:Macrolides; D046911:Macromolecular Substances; D012333:RNA, Messenger; D015375:Receptors, Interleukin-2; D014409:Tumor Necrosis Factor-alpha; C046785:bryostatin 1