A subcytotoxic dose of subtilase cytotoxin prevents lipopolysaccharide-induced inflammatory responses, depending on its capacity to induce the unfolded protein response.
Subtilase cytotoxin (SubAB) is the prototype of a newly identified family of AB(5) 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-kappaB 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-kappaB 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-alpha production associated with inhibition of NF-kappaB activation. SubA(A272)B, 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(A272)B, protected the mice from LPS-induced endotoxic lethality associated with reduced serum MCP-1 and TNF-alpha 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.
Harama
Daisuke
D
Department of Immunology, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan.
Koyama
Kensuke
K
Mukai
Mai
M
Shimokawa
Naomi
N
Miyata
Masanori
M
Nakamura
Yuki
Y
Ohnuma
Yuko
Y
Ogawa
Hideoki
H
Matsuoka
Shuji
S
Paton
Adrienne W
AW
Paton
James C
JC
Kitamura
Masanori
M
Nakao
Atsuhito
A
D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000517:prevention & control; D002460:Cell Line; D003603:Cytotoxins; D004721:Endoplasmic Reticulum / Q000473:pathology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D029968:Escherichia coli Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D007249:Inflammation / Q000139:chemically induced / Q000517:prevention & control*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018832:Molecular Chaperones / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D017510:Protein Folding / Q000187:drug effects*; D013381:Subtilisins / Q000008:administration & dosage / Q000494:pharmacology*
D003603:Cytotoxins; D000091342:Endoplasmic Reticulum Chaperone BiP; D029968:Escherichia coli Proteins; C000717248:Hspa5 protein, mouse; D008070:Lipopolysaccharides; D018832:Molecular Chaperones; D016328:NF-kappa B; D013381:Subtilisins; C527234:subtilase cytotoxin, E coli