IL-12 exacerbates rather than suppresses T helper 2-dependent pathology in the absence of endogenous IFN-gamma.
To assess the role of IFN-gamma in the in vivo regulation of Th subset differentiation by IL-12, schistosome egg-induced Th2 responses and granuloma formation were studied in IFN-gamma knock-out (gamma KO) mice in which the absence of endogenous IFN-gamma is assured. Rather than suppressing pathology and eosinophilia as observed in wild-type animals, exogenous IL-12 in egg-injected gamma KO mice exacerbated Th2-dependent granuloma formation while failing to reduce peak tissue eosinophilia. Similarly, instead of inhibiting its production, IL-12 caused a dramatic increase in serum IgE levels in gamma KO animals after egg injection. Although the suppressive effects of IL-12 on Th2 responses were blocked in the absence of IFN-gamma, lymphocyte proliferation and IL-2 production were enhanced, a phenomenon which may underlie the observed exacerbation of egg-induced pathology. These findings formally establish that IL-12 inhibits Th2 development indirectly in vivo through the stimulation of IFN-gamma synthesis. In contrast, its promotion of Th1-associated responses seems to be at least partly a result of the direct action of the cytokine.
Wynn
T A
TA
Host-Parasite Relations Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Jankovic
D
D
Hieny
S
S
Zioncheck
K
K
Jardieu
P
P
Cheever
A W
AW
Sher
A
A
D000818:Animals; D000947:Antigens, Helminth / Q000276:immunology; D016207:Cytokines / Q000235:genetics; D004804:Eosinophils / Q000276:immunology; D005260:Female; D015870:Gene Expression; D006099:Granuloma / Q000276:immunology; D007073:Immunoglobulin E / Q000097:blood; D007371:Interferon-gamma / Q000502:physiology*; D018664:Interleukin-12 / Q000494:pharmacology*; D008168:Lung / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010063:Ovum / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics; D011994:Recombinant Proteins; D012550:Schistosoma mansoni / Q000276:immunology*; D012555:Schistosomiasis mansoni / Q000276:immunology* / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000187:drug effects*
D000947:Antigens, Helminth; D016207:Cytokines; D012333:RNA, Messenger; D011994:Recombinant Proteins; D018664:Interleukin-12; D007073:Immunoglobulin E; D007371:Interferon-gamma