Cross-regulatory role of interferon-gamma (IFN-gamma), IL-4 and IL-10 in schistosome egg granuloma formation: in vivo regulation of Th activity and inflammation.
This study examined the relationship of IL-4, IL-10 and IFN-gamma with regard to the local granuloma (GR) and draining lymph node (LN) response to Schistosoma mansoni eggs. Synchronized GR were induced in naive and schistosome-infected mice at the vigorous (8 weeks) and late chronic (20 weeks) stages. In LN cultures, IL-10 and IFN production peaked on day 4 and was greatest for 8 week-infected mice. All GR cultures contained IFN, but compared with naive mice IL-10 production was accelerated at 8 weeks and abrogated at 20 weeks, consistent with expansion and abatement of Th2 activity. Cytokine neutralization was performed in egg-challenged, naive mice that were adoptively sensitized with lymphoid cells from 8 week-infected donors. GR size, GR macrophage tumour necrosis factor (TNF) production and egg antigen-elicited IL-2, IL-4, IL-5, IL-10 and IFN were examined on day 4 of GR formation. Anti-IFN augmented GR area by 40%, increased local IL-4 and IL-10, but decreased IFN and TNF production. In corresponding LN cultures, IFN decreased by about 50%, while IL-2, IL-4, IL-10 and IL-5 increased by nearly two-, four-, five- and six-fold, respectively. Anti-IL-10 did not affect GR size or GR cytokines, but abrogated GR area by 40%, along with a reduction in local IL-4 and TNF production. In LN, IL-4 depletion reduced IL-4 and IL-5 by 60-70% and increased IFN levels. These results support the notion of a cross-regulatory network in which IFN inhibits Th2 and IL-10 inhibits Th1 cells. IL-4 fosters Th2 cells differentiation in LN, but also performs a critical recruitment function in the eosinophil-rich schistosome egg-induced GR, whereas IFN contributes to enhanced GR macrophage function.
Chensue
S W
SW
Department of Pathology, Veterans Affairs Medical Centre, Ann Arbor, MI 48105.
Warmington
K S
KS
Ruth
J
J
Lincoln
P M
PM
Kunkel
S L
SL
D000818:Animals; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology; D005260:Female; D006099:Granuloma / Q000378:metabolism* / Q000469:parasitology* / Q000473:pathology; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology* / Q000494:pharmacology; D016753:Interleukin-10 / Q000097:blood / Q000276:immunology*; D015847:Interleukin-4 / Q000096:biosynthesis / Q000276:immunology*; D008099:Liver / Q000469:parasitology; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D008221:Lymphoid Tissue / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D051379:Mice; D008808:Mice, Inbred CBA; D010063:Ovum / Q000276:immunology / Q000469:parasitology; D011817:Rabbits; D011994:Recombinant Proteins / Q000494:pharmacology; D012550:Schistosoma mansoni / Q000276:immunology*; D012555:Schistosomiasis mansoni / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology*; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology*
D016207:Cytokines; D011994:Recombinant Proteins; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma