Interferon gamma-independent effects of interleukin 12 administered during acute or established infection due to Leishmania major.
Interleukin 12 (IL-12) is a powerful stimulus for the growth of activated T and natural killer cells, their generation of interferon gamma (IFN-gamma), and the differentiation of T helper type 1 (Th1) effector cells from naive precursors in vitro. These activities are consistent with the capacity of exogenous IL-12 to heal otherwise susceptible BALB/c mice infected with the intramacrophage parasite Leishmania major. Using this characterized model of CD4 cell subset differentiation, we examined the immunologic effects of IL-12 administered either at the time of infection, when naive T cells are primed, or after 14 days of infection, by which time CD4+ subset differentiation has occurred. Given with the inoculation of parasites, IL-12 induced IFN-gamma and IL-10 and markedly suppressed IL-4. Effects on IL-10 and IL-4 were comparable in mice with homozygous disruption of the IFN-gamma gene (IFN-gamma 0/0), and suppression of IL-4 was unchanged by administration of neutralizing anti-IL-10 antibody. Induction of IFN-gamma and IL-10 mRNA by IL-12 also occurred in infected SCID mice. Given after day 14 of infection, however, IL-12 not only induced IFN-gamma and IL-10 but also induced IL-4 in normal and IFN-gamma 0/0 mice. These data demonstrate direct effects of IL-12 independent of IFN-gamma, IL-10, and IL-4 and demonstrate that the ineffectiveness of IL-12 administered following infection with L. major correlates with resistance of differentiated Th2 cells to the IL-4-suppressing activity of IL-12.
Wang
Z E
ZE
Department of Medicine, University of California, San Francisco 94143.
Zheng
S
S
Corry
D B
DB
Dalton
D K
DK
Seder
R A
RA
Reiner
S L
SL
Locksley
R M
RM
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000008:administration & dosage; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000235:genetics*; D015870:Gene Expression; D007072:Immunoglobulin D / Q000276:immunology; D007371:Interferon-gamma / Q000502:physiology; D016753:Interleukin-10 / Q000502:physiology; D018664:Interleukin-12 / Q000008:administration & dosage*; D015847:Interleukin-4 / Q000235:genetics; D015848:Interleukin-5 / Q000502:physiology; D018320:Leishmania major / Q000276:immunology; D016773:Leishmaniasis, Cutaneous / Q000276:immunology*; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics; D011994:Recombinant Proteins; D013997:Time Factors
D000888:Antibodies, Anti-Idiotypic; D016207:Cytokines; D007072:Immunoglobulin D; D015848:Interleukin-5; D012333:RNA, Messenger; D011994:Recombinant Proteins; D016753:Interleukin-10; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma