Murine macrophage activation with resorcyclic acid lactones (RALs): comparison with diethylstilbestrol and 17β-estradiol

Abstract

Zearalane, a resorcylic acid lactone (RAL) derivative, activates murine macrophages (MΦ) in vivo and in vitro. Mouse MΦ incubated in vitro with different concentrations of zearalane released superoxide anion (O2−) on stimulation with either opsonized zymosan (Op-zym), phorbol myristate acetate (PMA), or Salmonella typhimurium. The levels of O2− released were similar to those released from MΦ incubated in vitro with supernatants enriched in macrophage-activating factors from concanavalin A-stimulated mouse spleen cells. In cobtrast, 17β-estradiol (E2) or diethylstilbestrol (DES) induced little or no enhancement of O2− release. Zearalane, dideoxyzearalane, DES and E2 were tested for induction of host resistance to S. typhimurium infection in mice. Treatment of mice with zearalane (9 mg/kg) resulted in at least 65% survival 4 days post-infection, compared to 10% survival of mice with vehicle alone, DES, or E2. Peritoneal and alveolar MΦ from the zearalane-treated mice released up to six times as much O2− on stimulation with Op-zym as MΦ from the other treatment groups. MΦ activation was observed for up to 7 days after intraperitoneal or subcutaneous administration of zearalane in either aqueous or organic vehicles. These results suggest that zearalane may enhance resistance to infection by increasing bactericidal activity due to increased release of toxic oxygen radicals by MΦ and mononuclear phagocytes. These effects differ from the immunosuppressive effects reported for DES and E2.