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Selective requirement for c-Rel during IL-12 P40 gene induction in macrophages

Sanjabi, Shomyseh and Hoffmann, Alexander and Liou, Hsiou-Chi and Baltimore, David and Smale, Stephen T. (2000) Selective requirement for c-Rel during IL-12 P40 gene induction in macrophages. Proceedings of the National Academy of Sciences of the United States of America, 97 (23). pp. 12705-12710. ISSN 0027-8424. http://resolver.caltech.edu/CaltechAUTHORS:SANpnas00

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Abstract

A major challenge in the study of gene regulation by NF-kappaB/Rel transcription factors is to understand, at the biological and mechanistic levels, the selective functions of individual Rel family members. To study selectivity, we have examined the NF-kappaB/Rel protein binding site (Rel site) within the IL-12 p40 promoter. IL-12 is a proinflammatory cytokine expressed by activated macrophages that serves as an essential inducer of T helper 1 cell development. In nuclear extracts from lipopolysaccharide-activated macrophages, the predominant Rel dimers capable of binding the IL-12 p40 Rel site were the p50/p65 and p50/c-Rel heterodimers and p50/p50 homodimer. The two heterodimers bound the site with comparable affinities and exhibited comparable transactivation activities. In striking contrast, p40 mRNA and protein concentrations were reduced dramatically in c-Rel(-/-) macrophages and only modestly in p65(-/-) macrophages. Other proinflammatory cytokine mRNAs and proteins were not significantly reduced in c-Rel(-/-) macrophages. These results reveal that a c-Rel-containing complex is an essential and selective activator of p40 transcription, which may reflect unique regulatory mechanisms or biological functions of IL-12. Furthermore, because selectivity was not observed in vitro or in transient transactivation experiments, these findings suggest that an understanding of the selectivity mechanism may require an analysis of the endogenous p40 locus.


Item Type:Article
Additional Information:Copyright © 2000 by the National Academy of Sciences. Contributed by David Baltimore, September 12, 2000. We thank Ranjan Sen for Rel expression plasmids. This work was supported by U.S. Public Health Service Grants R01-AI42549 (to D.B.) and T32-AI07323 (to S.S.). S.T.S. is an Investigator with the Howard Hughes Medical Institute. The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. §1734 solely to indicate this fact. Article published online before print: Proc. Natl. Acad. Sci. USA, 10.1073ypnas.230436397. Article and publication date are at www.pnas.orgycgiydoiy10.1073ypnas.230436397
Subject Keywords:NF-KAPPA-B, NECROSIS-FACTOR-ALPHA, IMMUNE-RESPONSES, EXHIBIT DEFECTS, MICE LACKING, INTERLEUKIN-12, TRANSCRIPTION, EXPRESSION, CELLS, ACTIVATION
Record Number:CaltechAUTHORS:SANpnas00
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:SANpnas00
Alternative URL:http://dx.doi.org/10.1073/pnas.230436397
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:883
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:01 Nov 2005
Last Modified:26 Dec 2012 08:41

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