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Infection and Immunity, September 2009, p. 3992-4001, Vol. 77, No. 9
0019-9567/09/$08.00+0     doi:10.1128/IAI.00015-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

The RD1 Locus in the Mycobacterium tuberculosis Genome Contributes to Activation of Caspase-1 via Induction of Potassium Ion Efflux in Infected Macrophages {triangledown}

Takeshi Kurenuma,1 Ikuo Kawamura,1* Hideki Hara,1 Ryosuke Uchiyama,2 Sylvia Daim,1 Sita Ramyamali Dewamitta,1 Shunsuke Sakai,1 Kohsuke Tsuchiya,1 Takamasa Nomura,1 and Masao Mitsuyama1

Department of Microbiology, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan,1 Department of Microbiology, Hyogo College of Medicine, Nishinomiya 663-8501, Japan2

Received 6 January 2009/ Returned for modification 25 March 2009/ Accepted 2 July 2009

A genomic locus called "region of difference 1" (RD1) in Mycobacterium tuberculosis has been shown to contribute to the generation of host protective immunity as well as to the virulence of the bacterium. To gain insight into the molecular mechanism, we investigated the difference in the cytokine-inducing ability between H37Rv and a mutant strain deficient for RD1 ({Delta}RD1). We found that RD1 is implicated in the production of caspase-1-dependent cytokines, interleukin-18 (IL-18) and IL-1β, from infected macrophages. The expression of these cytokines was similarly induced after infection with H37Rv and {Delta}RD1. However, the activation of caspase-1 was observed only in H37Rv-infected macrophages. The cytokine production and caspase-1 activation were induced independently of type I interferon receptor signaling events. We also found that the activation of caspase-1 was markedly inhibited with increasing concentrations of extracellular KCl. Furthermore, the production of IL-18 and IL-1β and caspase-1 activation were induced independently of a P2X7 purinergic receptor, and the inability of {Delta}RD1 in caspase-1 activation was compensated for by nigericin, an agent inducing the potassium ion efflux. Based on these results, we concluded that RD1 participates in caspase-1-dependent cytokine production via induction of the potassium ion efflux in infected macrophages.

* Corresponding author. Mailing address: Department of Microbiology, Kyoto University Graduate School of Medicine, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan. Phone: 81-75-753-4447. Fax: 81-75-753-4446. E-mail: ikuo_kawamura{at}mb.med.kyoto-u.ac.jp

{triangledown} Published ahead of print on 13 July 2009.

Editor: J. L. Flynn

Infection and Immunity, September 2009, p. 3992-4001, Vol. 77, No. 9
0019-9567/09/$08.00+0     doi:10.1128/IAI.00015-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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