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Infection and Immunity, May 2000, p. 2418-2423, Vol. 68, No. 5
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Transforming Growth Factor-beta Inhibits Lipopolysaccharide-Stimulated Expression of Inflammatory Cytokines in Mouse Macrophages through Downregulation of Activation Protein 1 and CD14 Receptor Expression

Kenichi Imai, Akira Takeshita, and Shigemasa Hanazawa*

Department of Oral Microbiology, Meikai University School of Dentistry, Keyakidai, Sakado City, Saitama 350-0283, Japan

Received 3 September 1999/Returned for modification 30 November 1999/Accepted 27 January 2000

The septic shock that occurs in gram-negative infections is caused by a cascade of inflammatory cytokines. Several studies showed that transforming growth factor-beta 1 (TGF-beta 1) inhibits this septic shock through suppression of expression of the lipopolysaccharide (LPS)-induced inflammatory cytokines. In this study, we investigated whether TGF-beta 1 inhibition of LPS-induced expression of inflammatory cytokines in the septic shock results from downregulation of LPS-stimulated expression of CD14, an LPS receptor. TGF-beta 1 markedly inhibited LPS stimulation of CD14 mRNA and protein levels in mouse macrophages. LPS-stimulated expression of CD14 was dramatically inhibited by addition of antisense, but not sense, c-fos and c-jun oligonucleotides. Since TGF-beta 1 pretreatment inhibited LPS-stimulated expression of c-fos and c-jun genes and also the binding of nuclear proteins to the consensus sequence of the binding site for activation protein 1 (AP-1), a heterodimer of c-Fos and c-Jun, in the cells, TGF-beta 1 inhibition of CD14 expression may be a consequence of downregulation of AP-1. LPS-stimulated expression of interleukin-1beta and tumor necrosis factor alpha genes in the cells was inhibited by addition of CD14 antisense oligonucleotide. Also, TGF-beta 1 inhibited the LPS-stimulated production of both inflammatory cytokines by the macrophages. In addition, TGF-beta 1 inhibited expression of the two cytokines in several organs of mice receiving LPS. Thus, our results suggest that TGF-beta 1 inhibition of LPS-stimulated inflammatory responses resulted from downregulation of CD14 and also may be a possible mechanism of TGF-beta 1 inhibition of LPS-induced septic shock.

* Corresponding author. Mailing address: Department of Oral Microbiology, Meikai University School of Dentistry, Keyakidai, Sakado City, Saitama 350-0283, Japan. Phone and fax: 81-492-79-2781. E-mail: hanazawa{at}dent.meikai.ac.jp.

Infection and Immunity, May 2000, p. 2418-2423, Vol. 68, No. 5
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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