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Infection and Immunity, August 2004, p. 4836-4847, Vol. 72, No. 8
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.8.4836-4847.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Proapoptotic Effect of Proteolytic Activation of Matrix Metalloproteinases by Streptococcus pyogenes Thiol Proteinase (Streptococcus Pyrogenic Exotoxin B)

Fumio Tamura,1 Rumiko Nakagawa,1 Teruo Akuta,1 Shigefumi Okamoto,2 Shigeyuki Hamada,2 Hiroshi Maeda,1 Shigetada Kawabata,2 and Takaaki Akaike1*

Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556,1 Department of Oral and Molecular Microbiology, Osaka University Graduate School of Dentistry, Suita-Osaka 565-0871, Japan2

Received 3 November 2003/ Returned for modification 15 January 2004/ Accepted 28 April 2004

Streptococcus pyogenes thiol proteinase, also known as streptococcal pyrogenic exotoxin B (SpeB), has been suggested to be a major virulence factor in S. pyogenes infection. SpeB was reported to induce apoptosis of host cells, but its mechanism of action is not yet fully understood. In this study, we examined the involvement of matrix metalloproteinases (MMPs) in SpeB-induced apoptosis. We first developed a large-scale preparation of recombinant SpeB and precursors of human MMP-9 and -2 (proMMPs) by using Escherichia coli Rosetta (DE3)pLysS and baculovirus-insect cell expression systems, respectively. Treatment with SpeB induced effective proteolytic activation of both proMMP-9 and -2. When RAW264 murine macrophages were incubated with SpeB-activated proMMP-9, the level of tumor necrosis factor alpha (TNF-{alpha}) in conditioned medium (CM), assessed by an enzyme immunoassay, was elevated. This increase was completely inhibited by addition of the MMP inhibitor SI-27 to the cell culture. The CM also produced marked induction of apoptosis of U937 human monocytic cells. Similarly, soluble Fas ligand (sFasL) was detected in CM of cultures of SW480 cells expressing FasL after treatment with SpeB-activated proMMPs; this CM also induced apoptosis in U937 cells. SpeB had a direct effect as well and caused the release of TNF-{alpha} and sFasL from the cells. SpeB-dependent production of MMP-9 and -2 and proapoptotic molecules (TNF-{alpha} and sFasL) was evident in a murine model of severe invasive S. pyogenes infection. These results suggest that SpeB or SpeB-activated MMPs contribute to tissue damage and streptococcal invasion in the host via extracellular release of TNF-{alpha} and sFasL.

* Corresponding author. Mailing address: Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan. Phone: (81) 96-373-5100. Fax: (81) 96-362-8362. E-mail: takakaik{at}gpo.kumamoto-u.ac.jp.

Editor: J. N. Weiser

Infection and Immunity, August 2004, p. 4836-4847, Vol. 72, No. 8
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.8.4836-4847.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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