Interleukin-12 can directly induce T-helper 1 responses in interferon-gamma (IFN-gamma) receptor-deficient mice, but requires IFN-gamma signalling to downregulate T-helper 2 responses.
An in vivo model of pulmonary granuloma formation around embolized schistosome eggs was investigated as an environment in which to analyse a role for interleukin-12 (IL-12) in the differentiation of T-helper 1 (Th1) and Th2 subsets. Specifically, mice deficient for the interferon-gamma receptor (IFN-gammaR-/-) were used to determine the role for IL-12 in the absence of IFN-gamma-mediated signalling. We show that recombinant IL-12 administered to IFN-gammaR-/- mice caused the up-regulation of mRNA for IFN-gamma in lung tissue, and the secretion of abundant IFN-gamma by in vitro-cultured lymph node cells in response to egg antigens. This indicates that IL-12 can act independently of IFN-gamma to induce the development of Th1 cells. Administration of rIL-12 to wild-type mice markedly reduced the secretion of Th2-associated cytokines, IL-4 and IL-5. However, these cytokines were not dramatically reduced in IFN-gammaR-/- mice treated with IL-12. We conclude that inhibition of these cytokines by IL-12 is primarily dependent upon effective IFN-gamma signalling, although abrogation of T-cell derived IL-10 appeared to be dependent upon IL-12. We also show that increases in mRNA for the beta2 subunit of the IL-12 receptor and the p40 subunit of IL-12 after rIL-12 treatment were lower in IFN-gammaR-/- mice, compared to wild-type mice, indicating that their expression was primarily dependent upon IFN-gamma with only a minor role for IL-12.
Mountford
A P
AP
Department of Biology, The University of York, York, UK.
Coulson
P S
PS
Cheever
A W
AW
Sher
A
A
Wilson
R A
RA
Wynn
T A
TA
D000818:Animals; D018929:Cell Culture Techniques; D015536:Down-Regulation / Q000276:immunology; D006099:Granuloma / Q000276:immunology; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology*; D018664:Interleukin-12 / Q000276:immunology*; D015847:Interleukin-4 / Q000096:biosynthesis; D015848:Interleukin-5 / Q000096:biosynthesis; D051379:Mice; D008815:Mice, Inbred Strains; D012333:RNA, Messenger / Q000235:genetics; D017471:Receptors, Interferon / Q000172:deficiency / Q000235:genetics; D011994:Recombinant Proteins / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012555:Schistosomiasis mansoni / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*; D000096743:Interferon gamma Receptor
D007371:Interferon-gamma; D018664:Interleukin-12; D015847:Interleukin-4; D015848:Interleukin-5; D012333:RNA, Messenger; D017471:Receptors, Interferon; D011994:Recombinant Proteins; D000096743:Interferon gamma Receptor