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Infection and Immunity, April 2008, p. 1547-1557, Vol. 76, No. 4
0019-9567/08/$08.00+0     doi:10.1128/IAI.01269-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Critical Involvement of Pneumolysin in Production of Interleukin-1 and Caspase-1-Dependent Cytokines in Infection with Streptococcus pneumoniae In Vitro: a Novel Function of Pneumolysin in Caspase-1 Activation

Shereen Shoma, Kohsuke Tsuchiya,^* Ikuo Kawamura, Takamasa Nomura, Hideki Hara, Ryosuke Uchiyama, Sylvia Daim, and Masao Mitsuyama

Department of Microbiology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto 606-8501, Japan

Received 15 September 2007/ Returned for modification 7 November 2007/ Accepted 8 January 2008

Pneumolysin is a pore-forming cytolysin known as a major virulence determinant of Streptococcus pneumoniae. This protein toxin has also been shown to activate the Toll-like receptor 4 (TLR4) signaling pathway. In this study, a mutant S. pneumoniae strain deficient in pneumolysin (ply) and a recombinant pneumolysin protein (rPLY) were constructed. Upon infection of macrophages in vitro, the ability to induce the production of interleukin-1 (IL-1), IL-1β, and IL-18 was severely impaired in the ply mutant, whereas there was no marked difference in the induction of tumor necrosis factor alpha (TNF-) and IL-12p40 between the wild type and the ply mutant of S. pneumoniae. When macrophages were stimulated with rPLY, the production of IL-1, IL-1β, and IL-18 was strongly induced in a TLR4-dependent manner, whereas lipopolysaccharide, a canonical TLR4 agonist, hardly induced these cytokines. In contrast, lipopolysaccharide was more potent than rPLY in inducing the production of TNF-, IL-6, and IL-12p40, the cytokines requiring no caspase activation. Activation of caspase-1 was observed in macrophages stimulated with rPLY but not in those stimulated with lipopolysaccharide, and the level of activation was higher in macrophages infected with wild-type S. pneumoniae than in those infected with the ply mutant. These results clearly indicate that pneumolysin plays a key role in the host response to S. pneumoniae, particularly in the induction of caspase-1-dependent cytokines.

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* Corresponding author. Mailing address: Department of Microbiology, Kyoto University Graduate School of Medicine, Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan. Phone: 81 75 753 4440. Fax: 81 75 753 4446. E-mail: tsuchiya{at}mb.med.kyoto-u.ac.jp

Published ahead of print on 14 January 2008.

Editor: J. N. Weiser

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Infection and Immunity, April 2008, p. 1547-1557, Vol. 76, No. 4
0019-9567/08/$08.00+0     doi:10.1128/IAI.01269-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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