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A Subcytotoxic Dose of Subtilase Cytotoxin Prevents Lipopolysaccharide-Induced Inflammatory Responses, Depending on its Capacity to Induce the Unfolded Protein Response¹

Daisuke Harama^*, Kensuke Koyama^*, Mai Mukai, Naomi Shimokawa^*, Masanori Miyata^*, Yuki Nakamura^*, Yuko Ohnuma^*, Hideoki Ogawa, Shuji Matsuoka, Adrienne W. Paton^¶, James C. Paton^¶, Masanori Kitamura^2, and Atsuhito Nakao^2,*,

^* Department of Immunology, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan; Department of Molecular Signaling, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan; Atopy Research Center, Juntendo University School of Medicine, Tokyo, Japan; Department of Pathology, Juntendo University School of Medicine, Tokyo, Japan; and ^¶ School of Molecular and Biomedical Science, University of Adelaide, South Australia, Australia

Subtilase cytotoxin (SubAB) is the prototype of a newly identified family of AB₅ cytotoxins produced by Shiga toxigenic Escherichia coli. SubAB specifically cleaves the essential endoplasmic reticulum (ER) chaperone BiP (GRP78), resulting in the activation of ER stress-induced unfolded protein response (UPR). We have recently shown that the UPR following ER stress can suppress cellular responses to inflammatory stimuli during the later phase, in association with inhibition of NF-B activation. These findings prompted us to hypothesize that SubAB, as a selective UPR inducer, might have beneficial effects on inflammation-associated pathology via a UPR-dependent inhibition of NF-B activation. The pretreatment of a mouse macrophage cell line, RAW264.7, with a subcytotoxic dose of SubAB-triggered UPR and inhibited LPS-induced MCP-1 and TNF- production associated with inhibition of NF-B activation. SubA_A272B, a SubAB active site mutant that cannot induce UPR, did not show such effects. In addition, pretreatment with a sublethal dose of SubAB, but not SubA_A272B, protected the mice from LPS-induced endotoxic lethality associated with reduced serum MCP-1 and TNF- levels and also prevented the development of experimental arthritis induced by LPS in mice. Collectively, although SubAB has been identified originally as a toxin associated with the pathogenesis of hemolytic uremic syndrome, the unique ability of SubAB to selectively induce the UPR may have the potential to prevent LPS-associated inflammatory pathology under subcytotoxic conditions.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by the grants from the Ministry of Education, Culture, Sports, Science, and Technology, Japan.

² Address correspondence and reprint requests to Dr. Masanori Kitamura, Department of Molecular Signaling, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan and Dr. Atsuhito Nakao, Department of Immunology, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan. E-mail addresses: masanori{at}yamanashi.ac.jp or anakao{at}yamanashi.ac.jp

³ Abbreviations used in this paper: SubAB, subtilase cytotoxin; ER, endoplasmic reticulum; UPR, unfolded protein response; WST, 2-(4-iodophenyl)-3-(4-nitrophenyl)-5-(2, 4-disulfophenyl)[²H]tetrazolium monosodium salt; CHOP, C/EBP homologous protein.

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