Induction of cytokines by toxins that have an identical RNA N-glycosidase activity: Shiga toxin, ricin, and modeccin.
Shiga toxin (Stx) has an A1-B5 subunit structure, and the A subunit is an RNA N-glycosidase that inhibits cellular protein synthesis. We previously reported that in Caco-2 cells Stx induced cytokines and that the RNA N-glycosidase activity was essential for the cytokine induction. It is known that the binding of the Stx-B subunit to its receptor glycolipid, Gb3, mediates an A subunit-independent signal in some types of cells, but the involvement of this signal in the cytokine induction is unclear. In this study, we investigated whether RNA N-glycosidase itself induces cytokines. IL-8 production was enhanced by Stx, ricin, and modeccin, three toxins that inhibit protein synthesis through an identical RNA N-glycosidase activity, but not by two other types of protein synthesis inhibitors, diphtheria toxin and cycloheximide. The RNA N-glycosidase-type toxins showed a similar induction pattern of cytokine mRNAs. Brefeldin A, a Golgi apparatus inhibitor, completely suppressed the cytokine induction by the toxins. Analysis by using inhibitors of toxin binding and also Stx-B subunit showed that the cytokine-inducing activity was independent of Gb3-mediated signaling. These results indicate that RNA N-glycosidase itself induces the cytokine production and that intracellular transport of toxins through the Golgi apparatus is essential for the activity.
Yamasaki
Chisato
C
Research Institute, International Medical Center of Japan, Tokyo 162-8655, Japan.
Nishikawa
Kiyotaka
K
Zeng
Xun-Ting
XT
Katayama
Yukie
Y
Natori
Yumiko
Y
Komatsu
Nobukazu
N
Oda
Tatsuya
T
Natori
Yasuhiro
Y
D000818:Animals; D020126:Brefeldin A / Q000378:metabolism; D018938:Caco-2 Cells; D002522:Chlorocebus aethiops; D016207:Cytokines / Q000378:metabolism*; D006017:Glycolipids / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D007785:Lactose / Q000378:metabolism; D008081:Liposomes / Q000378:metabolism; D009699:N-Glycosyl Hydrolases / Q000276:immunology / Q000378:metabolism*; D037121:Plant Lectins / Q000378:metabolism*; D021122:Protein Subunits / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000378:metabolism; D054788:Ribosome Inactivating Proteins; D054790:Ribosome Inactivating Proteins, Type 2; D012276:Ricin / Q000378:metabolism*; D022621:Shiga Toxin / Q000378:metabolism*; D013107:Sphingolipids / Q000378:metabolism; D014709:Vero Cells
D016207:Cytokines; D006017:Glycolipids; D016209:Interleukin-8; D008081:Liposomes; D037121:Plant Lectins; D021122:Protein Subunits; D011500:Protein Synthesis Inhibitors; D054790:Ribosome Inactivating Proteins, Type 2; D013107:Sphingolipids; C063288:globotriaosyl lysosphingolipid; D020126:Brefeldin A; C016004:modeccin; D022621:Shiga Toxin; D012276:Ricin; D009699:N-Glycosyl Hydrolases; D054788:Ribosome Inactivating Proteins; D007785:Lactose