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J. Biol. Chem., Vol. 281, Issue 36, 26041-26050, September 8, 2006
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NF-
B1 (p50) Homodimers Differentially Regulate Pro- and Anti-inflammatory Cytokines in Macrophages*
From the Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland 20742
NF-
B/Rel is a family of transcription factors whose activation has long been linked to the production of inflammatory cytokines. Here, we studied NF-B signaling in the regulation of the anti-inflammatory cytokine, interleukin-10 (IL-10). We identified a role for a single NF-B family member, NF-B1 (p50), in promoting the transcription of IL-10. The NF-B ciselement on IL-10 proximal promoter was located to –55/–46, where p50 can homodimerize and form a complex with the transcriptional co-activator CREB-binding protein to activate transcription. The other Rel family members appear to play a negligible role in IL-10 transcription. Mice lacking p50 were more susceptible to lethal endotoxemia, and macrophages taken from p50–/– mice exhibit skewed cytokine responses to lipopolysaccharide, characterized by decreased IL-10 and increased tumor necrosis factor and IL-12. Taken together, our studies demonstrate that NF-B1 (p50) homodimers can be transcriptional activators of IL-10. The reciprocal regulation of pro- and anti-inflammatory cytokine production by NF-B1 (p50) may provide potential new ways to manipulate the innate immune response.
Received for publication, March 9, 2006 , and in revised form, July 10, 2006.
* This work was supported in part by National Institutes of Health Grant AI49383. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S5.
1 To whom correspondence should be addressed: Dept. of Cell Biology and Molecular Genetics, University of Maryland, 1103 Microbiology Bldg., College Park, MD 20742. Tel.: 301-314-2594; Fax: 301-314-9489; E-mail: dmosser{at}umd.edu.
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