INTERLEUKIN-12 IS CRITICAL FOR INDUCTION OF NITRIC OXIDE-MEDIATED IMMUNOSUPPRESSION FOLLOWING VACCINATION OF MICE WITH ATTENUATED SALMONELLA-TYPHIMURIUM
Mg. Schwacha et Tk. Eisenstein, INTERLEUKIN-12 IS CRITICAL FOR INDUCTION OF NITRIC OXIDE-MEDIATED IMMUNOSUPPRESSION FOLLOWING VACCINATION OF MICE WITH ATTENUATED SALMONELLA-TYPHIMURIUM, Infection and immunity, 65(12), 1997, pp. 4897-4903
Studies from our laboratory have shown that infection of mice with an
attenuated strain of Salmonella typhimurium causes a marked suppressio
n in the capacity of splenocytes to generate an in vitro plaque-formin
g cell (PFC) response to sheep erythrocytes. The suppression has been
shown to be mediated by mature, adherent macrophages (M phi s) and non
adherent, precursor M phi s. Nitric oxide has been identified as the s
uppressor factor. The present study investigated the role of interleuk
in-12 (IL-12) in the generation of nitric oxide-mediated immunosuppres
sion in this model. Salmonella inoculation resulted in marked suppress
ion of PFC responses and high levels of nitrite production. When mice
were treated with anti-IL-12 prior to inoculation, nitrite levels in s
plenocyte cultures were reduced by 75% and the suppression of PFC resp
onses,vas prevented. The nonadherent splenocyte fraction from Salmonel
la-inoculated mice, which contains precursor M phi s and is weakly imm
unosuppressive, was treated with IL-12 in vitro. IL-12 augmented the c
apacity of this fraction to suppress PFC responses by normal splenocyt
es in a coculture system. Additionally, IL-12 induced nitrite and gamm
a interferon (IFN-gamma) production in a dose-dependent manner. Treatm
ent with anti-IFN-gamma blocked nitrite production and suppression, in
dicating that IFN-gamma is an important intermediary in the pathway of
IL-12-induced immunosuppression. These results indicate that IL-12 is
critical for the induction of nitric oxide-mediated immunosuppression
following S. typhimurium inoculation and, through its ability to stim
ulate IFN-gamma production, can induce nitric oxide-producing suppress
or M phi s.