Interleukin‐12 can directly induce T‐helper 1 responses in interferon‐γ (IFN‐γ) receptor‐deficient mice, but requires IFN‐γ signalling to downregulate T‐helper 2 responses

• Published in: Immunology Vol. 97; no. 4; pp. 588 - 594
• Main Authors: Mountford, Coulson, Cheever, Sher, A., Wilson, R. A., Wynn
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01.08.1999; Blackwell Science Inc
• Subjects: Animals; Cell Culture Techniques; Down-Regulation - immunology; Granuloma - immunology; Interferon gamma Receptor; Interferon-gamma - genetics; Interferon-gamma - immunology; Interleukin-12 - immunology; Interleukin-4 - biosynthesis; Interleukin-5 - biosynthesis; Mice; Mice, Inbred Strains; Original; Receptors, Interferon - deficiency; Receptors, Interferon - genetics; Recombinant Proteins - immunology; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Schistosomiasis mansoni - immunology; Th1 Cells - immunology; Th2 Cells - immunology
• ISSN: 0019-2805; 1365-2567
• DOI: 10.1046/j.1365-2567.1999.00832.x

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‐γ receptor (IFN‐γR−/–) were used to determine the role for IL‐12 in the absence of IFN‐γ‐mediated signalling. We show that recombinant IL‐12 administered to IFN‐γR−/– mice caused the up‐regulation of mRNA for IFN‐γ in lung tissue, and the secretion of abundant IFN‐γ by in vitro‐cultured lymph node cells in response to egg antigens. This indicates that IL‐12 can act independently of IFN‐γ 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‐γR−/– mice treated with IL‐12. We conclude that inhibition of these cytokines by IL‐12 is primarily dependent upon effective IFN‐γ 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 β2 subunit of the IL‐12 receptor and the p40 subunit of IL‐12 after rIL‐12 treatment were lower in IFN‐γR−/– mice, compared to wild‐type mice, indicating that their expression was primarily dependent upon IFN‐γ with only a minor role for IL‐12.