Adiponectin inhibits inflammatory cytokines production by Beclin-1 phosphorylation and B-cell lymphoma 2 mRNA destabilization: role for autophagy induction

作者：Pun Nirmala Tilija; Park Pil Hoon^*

来源：British Journal of Pharmacology, 2018, 175(7): 1066-1084.

DOI：10.1111/bph.14144

BACKGROUND AND PURPOSE
Adiponectin potently suppresses inflammatory mediator production. Autophagy is known to play a critical role in the modulation of inflammatory responses by adiponectin. However, the underlying mechanisms are not clearly understood. Interaction between Beclin-1 and B-cell lymphoma 2 (Bcl-2) is a critical event in autophagy induction. We examined the effects of globular adiponectin (gAcrp) on the Beclin-1/Bcl-2 association and its underlying mechanisms.
EXPERIMENTAL APPROACH
The effect of gAcrp on the interaction between Beclin-1 and Bcl-2 was examined by immunoprecipitation followed by Western blotting. To elucidate the underlying mechanisms, we determined the effects of gAcrp on Beclin-1 phosphorylation and Bcl-2 mRNA stability, and investigated their role in the suppression of inflammatory mediators using pharmacological inhibitors and transient target gene knockdown.
KEY RESULTS
Globular adiponectin disrupted the association between Beclin-1 and Bcl-2 and increased Beclin-1 phosphorylation at Thr(119), critical residue for binding with Bcl-2, via a death-associated protein kinase-1 (DAPK1)-dependent mechanism. Moreover, gAcrp reduced Bcl-2 expression via Bcl-2 mRNA destabilization, without significantly affecting Bcl-2 promoter activity and protein degradation, which was mediated by tristetraprolin (TTP) induction. Finally, DAPK1 and TTP were shown to play key roles in gAcrp-induced autophagosome formation and suppression of LPS-stimulated TNF- and IL-1 expression.
CONCLUSION AND IMPLICATIONS
Beclin-1 phosphorylation and Bcl-2 mRNA destabilization mediated by DAPK1 and TTP are crucial events leading to autophagy and the suppression of inflammatory cytokine production by gAcrp. These results provide novel mechanisms underlying adiponectin's modulation of inflammatory responses. DAPK and TTP are potential therapeutic targets for the management of inflammation.

• 出版日期2018-4