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Research Article Free access | 10.1172/JCI1050

Inhibition of IL-12 production by 1,25-dihydroxyvitamin D3. Involvement of NF-kappaB downregulation in transcriptional repression of the p40 gene.

D D'Ambrosio, M Cippitelli, M G Cocciolo, D Mazzeo, P Di Lucia, R Lang, F Sinigaglia, and P Panina-Bordignon

Roche Milano Ricerche, I-20132, Milan, Italy. dambrod@dibit.hsr.it

Find articles by D'Ambrosio, D. in: PubMed | Google Scholar

Roche Milano Ricerche, I-20132, Milan, Italy. dambrod@dibit.hsr.it

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Roche Milano Ricerche, I-20132, Milan, Italy. dambrod@dibit.hsr.it

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Roche Milano Ricerche, I-20132, Milan, Italy. dambrod@dibit.hsr.it

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Roche Milano Ricerche, I-20132, Milan, Italy. dambrod@dibit.hsr.it

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Roche Milano Ricerche, I-20132, Milan, Italy. dambrod@dibit.hsr.it

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Roche Milano Ricerche, I-20132, Milan, Italy. dambrod@dibit.hsr.it

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Roche Milano Ricerche, I-20132, Milan, Italy. dambrod@dibit.hsr.it

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Published January 1, 1998 - More info

Published in Volume 101, Issue 1 on January 1, 1998
J Clin Invest. 1998;101(1):252–262. https://doi.org/10.1172/JCI1050.
© 1998 The American Society for Clinical Investigation
Published January 1, 1998 - Version history
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Abstract

Interleukin 12 (IL-12), produced by myelomonocytic cells, plays a pivotal role in the development of T helper 1 (Th1) cells, which are involved in the pathogenesis of chronic inflammatory autoimmune disorders. 1,25-Dihydroxyvitamin D3 [1,25(OH)2D3] inhibits IL-12 production by activated macrophages and dendritic cells, thus providing a novel interpretation to its immunosuppressive properties. 1,25(OH)2D3 significantly inhibits mRNA expression for both IL-12 p35 and p40 subunits acting at the transcriptional level. The effect of 1,25(OH)2D3 on p40 promoter activation was analyzed by cotransfecting monocytic RAW264.7 cells with p40 promoter/reporter constructs and expression vectors for vitamin D3 receptor (VDR) and/or retinoid X receptor (RXRalpha). We observed transcriptional repression of the p40 gene by 1,25(OH)2D3, which required coexpression of VDR with RXR and an intact VDR DNA-binding domain. The repressive effect maps to a region in the p40 promoter containing a binding site for NF-kappaB (p40-kappaB). Deletion of the p40-kappaB site abrogates part of the inhibitory effect on the p40 promoter, confirming the functional relevance of this site. Activation of monocytic THP-1 cells in the presence of 1,25(OH)2D3 results in reduced binding to the p40-kappaB site. Thus, 1,25(OH)2D3 may negatively regulate IL-12 production by downregulation of NF-kappaB activation and binding to the p40-kappaB sequence.

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  • Version 1 (January 1, 1998): No description

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