C-Rel Regulates Interleukin 12 P70 Expression in Cd8+ Dendritic Cells by Specifically Inducing p35 Gene Transcription

doi:10.1084/jem.194.8.1021

Published 15 October 2001. doi:10.1084/jem.194.8.1021

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© The Rockefeller University Press, 0022-1007/2001/10/1021/ $5.00
The Journal of Experimental Medicine, Volume 194, Number 8, October 15, 2001 1021-1032

Original Article

C-Rel Regulates Interleukin 12 P70 Expression in Cd8⁺ Dendritic Cells by Specifically Inducing p35 Gene Transcription

Raelene Grumont^a, Hubertus Hochrein^a, Meredith O'Keeffe^a, Raffi Gugasyan^a, Christine White^a, Irina Caminschi^a, Wendy Cook^a, and Steve Gerondakis^a

^a The Walter and Eliza Hall Institute of Medical Research, The Royal Melbourne Hospital, Victoria 3050, Australia
The Walter and Eliza Hall Institute of Medical Research, Post Office The Royal Melbourne Hospital, Victoria 3050, Australia.61-3-9347085261-3-93452542

gerondakis{at}wehi.edu.au

Interleukin 12 (IL-12) is a 70-kD proinflammatory cytokine producedby antigen presenting cells that is essential for the inductionof T helper type 1 development. It comprises 35-kD (p35) and40-kD (p40) polypeptides encoded by separate genes that areinduced by a range of stimuli that include lipopolysaccharide(LPS), DNA, and CD40 ligand. To date, the regulation of IL-12expression at the transcriptional level has mainly been examinedin macrophages and restricted almost exclusively to the p40gene. Here we show that in CD8⁺ dendritic cells, major producersof IL-12 p70, the Rel/nuclear factor (NF)- ${kappa}$ B signaling pathwayis necessary for the induction of IL-12 in response to microbialstimuli. In contrast to macrophages which require c-Rel forp40 transcription, in CD8⁺ dendritic cells, the induced expressionof p35 rather than p40 by inactivated Staphylococcus aureus,DNA, or LPS is c-Rel dependent and regulated directly by c-Relcomplexes binding to the p35 promoter. This data establishesthe IL-12 p35 gene as a new target of c-Rel and shows that theregulation of IL-12 p70 expression at the transcriptional levelby Rel/NF- ${kappa}$ B is controlled through both the p35 and p40 genesin a cell type–specific fashion.

Key Words: c-rel • IL-12 • dendritic cells • p35 gene • transcription

R. Grumont and H. Hochrein contributed equally to this work.

H. Hochrein's present address is Medical Microbiology, Departmentof Immunology and Hygiene, Technical University of Munich, MunichD-81675, Germany.

Abbreviations used in this paper: DC, dendritic cell; EMSA,electrophoretic mobility shift assay; NF, nuclear factor; SAC,Staphylococcus aureus.

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