Interleukin (IL)-4 Is a Major Regulatory Cytokine Governing Bioactive IL-12 Production by Mouse and Human Dendritic Cells

doi:10.1084/jem.192.6.823

Published online 11 September 2000.

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© The Rockefeller University Press, 0022-1007/2000/9/823/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 6, September 18, 2000 823-834

Original Article

Interleukin (IL)-4 Is a Major Regulatory Cytokine Governing Bioactive IL-12 Production by Mouse and Human Dendritic Cells

Hubertus Hochrein^a, Meredith O'Keeffe^a, Thomas Luft^b, Stéphane Vandenabeele^a, Raelene J. Grumont^a, Eugene Maraskovsky^b, and Ken Shortman^a
^a From The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3050, Australia
^b Ludwig Institute for Cancer Research, Austin & Repatriation Medical Centre, Heidelberg, Victoria 3084, Australia

Correspondence to: Ken Shortman, The Walter and Eliza Hall Institute of Medical Research, Post Office Royal Melbourne Hospital, Victoria 3050, Australia. Tel:61-3-9345-2531 Fax:61-3-9347-0852 E-mail:shortman{at}wehi.edu.au.

Interleukin (IL)-12 may be secreted as a bioactive T helpertype 1 (Th1) cell–inducing heterodimer, as a monomer,or as an antagonistic homodimer. We analyzed the IL-12 producedby mouse splenic dendritic cells (DCs), human thymic DCs, andcultured human monocyte-derived DCs. IL-12 production requiredboth a microbial or T cell–derived stimulus and an appropriatecytokine milieu. The different IL-12 forms were differentiallyregulated by the cytokines present rather than the stimulusused. IL-4 alone or together with granulocyte/macrophage colony-stimulatingfactor or interferon ${gamma}$ effectively enhanced the production ofthe bioactive heterodimer and selectively reduced the antagonistichomodimer of IL-12. Therefore, IL-4, the major Th2-driving cytokine,provides a negative feedback causing DCs to produce the majorTh1-inducing cytokine, bioactive IL-12.

Key Words: granulocyte/macrophage colony-stimulating factor, homodimericinterleukin 12, T helper type 1, T helper type 2, interferon ${gamma}$

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