Jp. Kelly et Gj. Bancroft, ADMINISTRATION OF INTERLEUKIN-10 ABOLISHES INNATE RESISTANCE TO LISTERIA-MONOCYTOGENES, European Journal of Immunology, 26(2), 1996, pp. 356-364
We have used severe-combined immunodeficient (SCID) mice resulted in s
ecretion of interferon (IFN)-gamma from natural killer cells in vitro.
This response was enhanced up to 15-fold in the presence of exogenous
IL-2 but was completely ablated by addition of IL-10 with and IC50 of
<0.5 U/ml. Infection of SCID mice with viable Listeria in vivo result
ed in a prolonged course of infection eventually causing death by 12-1
4 days, whereas daily administration of IL-10 increased bacterial repl
ication in the liver and spleen by up to 1000-fold resulting in death
by day 4 post-infection. The immunosuppressive actions of IL-10 in viv
o were also observed in immunocompetent BALB/c mice. where doses as lo
w as 100 U/day converted a sublethal infection to 100% mortality. To s
tudy the events controlling expression of endogenous IL-10. peritoneal
macrophage monolayers were challenged with Listeria after pre-incubat
ion with a panel of recombinant cytokines. IFN-gamma primed macrophage
s for enhanced tumor necrosis factor (TNF) secretion. but inhibited IL
-10 production, whereas granulocyte/macrophage colony-stimulating fact
or (CSF). macrophage CSF and also IL-4 enhanced macrophage IL-10 respo
nses after ingestion of Listeria in vitro. Finally, monoclonal antibod
y neutralization of IFN-gamma during infection of SCID mice with Liste
ria inhibited TNF-alpha mRNA. but augmented expression of IL-10 mRNA i
n infected tissues. These results demonstrate that exogenous IL-10 is
a potent immunosuppressive cytokine in the context of infection with a
n intracellular bacterium and that expression of endogenous IL-10 vers
us TNF is differentially regulated by the cytokine environment of the
macrophage.