Therapeutic concentrations of glucocorticoids suppress the antimicrobial activity of human macrophages without impairing their responsiveness to gamma interferon.

Abstract

By exposing human blood-derived macrophages and alveolar macrophages in vitro to dexamethasone, we showed in these studies that glucocorticoids markedly suppress the antimicrobial activity of macrophages but not macrophage activation by lymphokines. As little as 2.5 X 10-8 mol/liter of dexamethasone prevented macrophages from inhibiting germination of Aspergillus spores or from eliminating ingested bacteria such as Listeria, Nocardia, or Salmonella. Damage to macrophage function was inhibited by progesterone and appeared to be receptor-mediated. In accordance with in vivo observations, dexamethasone required 24-36 h to suppress antimicrobial activity. While glucocorticoids interfered with base-line activity of macrophages, dexamethasone concentrations comparable to drug levels in patients had no effect on macrophage activation. Proliferating lymphocytes and 'y-interferon thus increased the antimicrobial activity of phagocytes exposed to glucocorticoids over that of control cells. Macrophage activation and correction of the dexamethasone effect by 'y-interferon, however, was dependent on the pathogen. The lymphokine enhanced the antimicrobial activity of dexamethasone-treated macrophages against Listeia and Salmonella but not against Aspergillus or Nocardia. Dexamethasone-induced damage to the antimicrobial activity of human macrophages in vitro parallels observations that glucocorticoids render laboratory animals susceptible to listeriosis and aspergillosis by damaging resident macrophages. Suppression of macrophage antimicrobial activity should thus be considered when treating patients with glucocorticoids; its prevention byinterferon might be beneficial for some but not all pathogens.

Interferon-γ Augments Acute Macrophage-Mediated Renal Injury Via a Glucocorticoid-Sensitive Mechanism

“…Indeed, a number of macrophage responses to IFN-␥ are not inhibited by glucocorticoids. IFN-␥ upregulation of Fc-R in human monocytes is enhanced by Dex (41,42), therapeutic concentrations of glucocorticoids have been shown to suppress the antimicrobial activity of human macrophages without impairing their responsiveness to IFN-␥ (43,44), and IFN-␥-induced macrophage antibody-dependent cellular cytotoxicity is not inhibited by Dex (45). In our studies, Dex inhibited the ability of IFN-␥-activated macrophages to accumulate within the glomerulus and thus prevented renal injury.…”

T Cell Vaccination in Mice with Invasive Pulmonary Aspergillosis

“…Resident alveolar macrophages ingest and kill resting conidia, largely through nonoxidative mechanisms, while neutrophils use oxygen-dependent mechanisms to attack hyphae germinating from conidia that escape macrophage surveillance (13,14). The effectiveness of this system is evident from the observation that challenge with even large numbers of conidia fails to cause disease in immunocompetent animals (17), and recognized major risk factors in humans are defects in phagocyte functions, such as those occurring in chronic granulomatous disease (18,19), cortisone-induced suppression of macrophage conidiocidal activity (20,21), and chemotherapy-induced neutropenia (22). Increased risk of a chronic form of IPA that is independent of neutropenia and corticosteroid therapy has been noticed in patients with HIV (8), who also showed a defective effector activity of neutrophils against A. fumigatus (23).…”

Macrophage Inflammatory Protein-1α Is a Critical Mediator of Host Defense Against Invasive Pulmonary Aspergillosis in Neutropenic Hosts

“…In experimental animals, alveolar and peritoneal macrophages bind and engulf Aspergillus fumigatus conidia in vitro (10,(13)(14)(15) and produce IL-1 and TNF when exposed to either conidia or hyphae (16). In vitro studies of human peripheral monocytes (17,18), monocyte-derived macrophages (19), and alveolar macrophages (20,21) have also shown these cells to phagocytose conidia and kill both conidial and hyphal forms of A. fumigatus. One study has suggested a role for splenic macrophages in acquired immunity against i.v.…”