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The Antineoplastic Agent Bryostatin-1 Induces Proinflammatory Cytokine Production in Human Monocytes - Synergy With Interleukin-2 and Modulation of Interleukin-2r-Gamma Chain Expression

  1. Author:
    Bosco, M. C.
    Rottschafer, S.
    Taylor, L. S.
    Ortaldo, J. R.
    Longo, D. L.
    Espinozadelgado, I.

  2. Author Address

    Espinozadelgado I LOUISIANA STATE UNIV MED CTR DEPT MED 1542 TULANE AVE NEW ORLEANS, LA 70112 USA LOUISIANA STATE UNIV MED CTR DEPT MED NEW ORLEANS, LA 70112 USA NCI FREDERICK CANC RES & DEV CTR EXPT IMMUNOL LAB FREDERICK, MD USA SAIC FREDERICK INTRAMURAL RES SUPPORT PROGRAM FREDERICK, MD USA NIA GERONTOL RES CTR BALTIMORE, MD 21224 USA
    1. Year: 1997
  2. Journal: Blood
    1. 89
    2. 9
    3. Pages: 3402-3411
  4. Type of Article: Article
  1. Abstract:

    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-1 beta, 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-2R gamma 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 PMC 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. [References: 58]

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