11β-HSD1 modulates LPS-induced innate immune responses in adipocytes by altering expression of PTEN.
Inhibition of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) represents a therapeutic target for treating hyperglycemia in type 2 diabetes. Here, we investigate the effects of 11β-HSD1 on the innate immune response of adipocytes to produce proinflammatory cytokines. The 11β-HSD1 inhibitor emodin, or 11β-HSD1-targeted small interfering RNA, dose dependently suppressed IL-6, IL-1β, and TNF-α expression in lipopolysaccharide-treated 3T3-L1 adipocytes. Inhibiting 11β-HSD1 also reduced phosphatase and tensin homologue (PTEN) expression, a negative regulator of phosphatidylinositol 3-kinase effects, whereas 1pM cortisone or dexamethasone induced IL-6 and PTEN levels. PTEN-targeted small interfering RNA decreased IL-6, IL-1β, and TNF-α without affecting 11β-HSD1 levels. Correspondingly, emodin increased phosphorylated protein kinase B (p-PKB) (Ser473) to PKB ratio but not p-PKB (Thr308) to PKB ratio. Emodin did not increase the p-PKB (Ser473) to PKB ratio when the rapamycin-insensitive companion of mTOR was depleted, further supporting the involvement of mammalian target of rapamycin complex 2 in PKB phosphorylation. Moreover, emodin suppressed phosphorylated inhibitor of κB α (p-IκBα) to IκBα ratio and reduced nuclear factor κ B subunit p50 in the nuclear fraction. In contrast, 1pM cortisone or dexamethasone decreased p-PKB (Ser473) to PKB ratio, increased p-IκBα to IκBα ratio, and increased nuclear NF-κB subunit p50. Additionally, wortmannin had similar effects on IL-6, p-PKB (Ser473) to PKB ratio, and p-IκBα to IκBα ratio as 1pM cortisone or dexamethasone. Finally, emodin treatment of streptozotocin diabetic rats on a high-fat diet reduced levels of IL-6, PTEN, Cluster of Differentiation 68, and the ratio of p-IκBα to IκBα in visceral fat, indicating that our findings in vitro may also apply to visceral fat in vivo. Together, these results suggest that inhibiting 11β-HSD1 reduces lipopolysaccharide-induced proinflammatory innate immune responses in adipocytes by down-regulating PTEN expression, leading to activation of the PI3K/PKB pathway.
Centre of Biomedical Research and Development (W.L., X.T., Q.X., K.C., Y.W., J.D., S.Z., J.B., G.H.), Fujian University of Traditional Chinese Medicine, Minhou Shangjie, Fuzhou, 350108, China; and School of Biological Sciences (S.Z.), Faculty of Science, University of Auckland, 1142, Auckland, New Zealand.
Wenfang
W
Lai
Xue
X
Tian
Qing
Q
Xiang
Kedan
K
Chu
Yicong
Y
Wei
Jingti
J
Deng
Shaoping
S
Zhang
John
J
Brown
Guizhu
G
Hong
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D059305:Diet, High-Fat; D004642:Emodin / Q000494:pharmacology; D007113:Immunity, Innate / Q000187:drug effects / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering; D051381:Rats
D016207:Cytokines; D008070:Lipopolysaccharides; D034741:RNA, Small Interfering; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D051059:PTEN Phosphohydrolase; D004642:Emodin