Anti-inflammatory Subtilase Cytotoxin Up-regulates A20 Through the Unfolded Protein Response

We recently reported that subtilase cytotoxin (SubAB) has the potential to attenuate experimental models of inflammatory diseases [3]. Currently, little is known about underlying mechanisms involved in this therapeutic effect. In the present report, we show that SubAB induces A20, the endogenous negative regulator of NF-kappaB, in vitro and in vivo. This stimulatory effect occurred at the transcriptional level, and SubAB induced activation of the A20 promoter. We found that, in the early phase, SubAB triggered activation of NF-kappaB in a dose-dependent manner. Blockade of NF-kappaB abrogated expression of A20 by SubAB. SubAB rapidly triggered the unfolded protein response (UPR), and induction of the UPR by other agents (thapsigargin and A23187) mimicked the stimulatory effects of SubAB, both on NF-kappaB and on A20. The induction of A20 by thapsigargin was correlated with activation of the A20 promoter, which was not observed in the kappaB-mutated A20 promoter. Furthermore, induction of A20 by SubAB was substantially attenuated by treatment with different chemical chaperones. These results elucidated for the first time that the anti-inflammatory SubAB has the potential to induce A20 through the UPR-NF-kappaB-dependent pathway.