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The antineoplastic agent bryostatin-1 induces proinflammatory cytokine
production in human monocytes: synergy with interleukin-2 and modulation of
interleukin-2Rgamma chain expression
MC Bosco, S Rottschafer, LS Taylor, JR Ortaldo, DL Longo and I Espinoza-Delgado
Intramural Research Support Program, SAIC Frederick, MD, USA.
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.
Volume 89,
Issue 9,
pp. 3402-3411,
05/01/1997
Copyright © 1997 by The American Society of Hematology
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