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Clinical and Vaccine Immunology, August 2006, p. 876-883, Vol. 13, No. 8
1071-412X/06/$08.00+0     doi:10.1128/CVI.00075-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Regulation of Lipopolysaccharide-Induced Interleukin-12 Production by Activation of Repressor Element GA-12 through Hyperactivation of the ERK Pathway

Shinji Saito, Motohiro Matsuura,^* and Yoshikazu Hirai

Department of Infection and Immunity, School of Medicine, Jichi Medical University, Tochigi, Japan

Received 20 February 2006/ Returned for modification 24 April 2006/ Accepted 13 June 2006

Interleukin-12 (IL-12) functions as a representative lipopolysaccharide (LPS) mediator in both innate and adaptive immunity. We investigated the regulation of LPS-induced IL-12 production by mouse macrophages. In response to LPS, peritoneal macrophages produced bioactive IL-12 p70, a heterodimer (p40/p35) of subunits, but macrophage lines such as J774.1 and RAW264.7 did not. Induction of the p35 subunit was impaired in both cell lines, and additional impairment of p40 induction was observed in RAW264.7 cells. These results suggest that some negative regulatory mechanisms against LPS-induced IL-12 p40 production are constitutively functioning in RAW264.7 cells but not in the other types of cells. Activation of GA-12 (a repressor element of IL-12 p40), rather than suppression of promoter elements, such as binding sites for NF-B, AP-1, and IRF-1, was detected in LPS-stimulated RAW264.7 cells, accompanying hyperactivation of extracellular signal-related kinase (ERK). When ERK activation was suppressed by an inhibitor (U0126), production of p40 rose from an undetectable to a substantial level and GA-12 activation decreased. In peritoneal macrophages, stimulation with a high dose of LPS reduced p40 production with enhanced activation of ERK. Pretreatment of the cells with phorbol myristate acetate to enhance ERK activation reduced p40 production in response to the optimal LPS stimulation. Taken together, these results demonstrate that hyperactivation of the ERK pathway plays a role in upstream signaling for the activation of GA-12, leading to the repression of IL-12 p40 production in mouse macrophages.

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* Corresponding author. Mailing address: Department of Infection and Immunity, School of Medicine, Jichi Medical University, 3311-1, Yakushiji, Shimotsuke, Tochigi 329-0498, Japan. Phone: 81-285-58-7332. Fax: 81-285-44-1175. E-mail: mmatsuur{at}jichi.ac.jp.

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Clinical and Vaccine Immunology, August 2006, p. 876-883, Vol. 13, No. 8
1071-412X/06/$08.00+0     doi:10.1128/CVI.00075-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

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