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 8 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

Correspondence to: Steve Gerondakis, The Walter and Eliza Hall Institute of Medical Research, Post Office The Royal Melbourne Hospital, Victoria 3050, Australia. Tel:61-3-93452542 Fax:61-3-93470852 E-mail: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

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