|Title||Proinflammatory cytokine induction of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in human adipocytes is mediated by MEK, C/EBPβ, and NF-κB/RelA.|
|Publication Type||Journal Article|
|Year of Publication||2014|
|Authors||Esteves CL, Kelly V, Breton A, Taylor AI, West CC, Donadeu FXavier, Péault B, Seckl JR, Chapman KE|
|Journal||J Clin Endocrinol Metab|
|Date Published||2014 Jan|
|Keywords||11-beta-Hydroxysteroid Dehydrogenase Type 1, Adipocytes, Adult, CCAAT-Enhancer-Binding Protein-beta, Cells, Cultured, Cytokines, Enzyme Induction, Extracellular Signal-Regulated MAP Kinases, Female, Humans, Infant, Inflammation Mediators, Male, Middle Aged, NF-kappa B, Transcription Factor RelA, Young Adult|
CONTEXT: Levels of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which regenerates active glucocorticoids, are selectively elevated in adipose tissue in human obesity and metabolic syndrome, both conditions associated with chronic low-grade inflammation. 11β-HSD1 expression is induced by proinflammatory cytokines in a variety of cell types, including in human adipocytes differentiated in vitro.
OBJECTIVE: Our objective was to determine the mechanisms by which proinflammatory cytokines induce 11β-HSD1 in human adipocytes.
RESULTS: The proinflammatory cytokines IL-1α (10 ng/mL) and TNFα (20 ng/mL) increased 11β-HSD1 mRNA levels in human primary adipocyte fractions and Simpson-Golabi-Behmel syndrome (SGBS) adipocytes (P<.001). Inhibition of the MAPK/ERK kinase (MEK) attenuated CCAAT/enhancer binding protein (C/EBP) β phosphorylation at Thr235 and IL-1α/TNFα induction of 11β-HSD1 (P≤.007). The small interfering RNA-mediated knockdown of C/EBPβ and nuclear factor (NF)-κB/RelA or inhibition of NF-κB/RelA also attenuated cytokine induction of 11β-HSD1 (P≤.001). Moreover, induction of 11β-HSD1 by IL-1α in SGBS cells was associated with nuclear localization of C/EBPβ and NF-κB/RelA. Chromatin immunoprecipitation experiments showed C/EBPβ and NF-κB/RelA located to the 11β-HSD1 promoter in human adipose tissue. Treatment of adipocyte fractions or SGBS adipocytes with metformin or acetylsalicylic acid, which target C/EBPβ and NF-κB/RelA signaling, attenuated the IL-1α induction of 11β-HSD1 (P≤.002).
CONCLUSIONS: Increased proinflammatory signaling in inflamed adipose tissue may mediate elevated 11β-HSD1 expression at this site via MEK, C/EBPβ, and NF-κB/RelA. These molecules/signaling pathways are, therefore, potential targets for drugs, including metformin and acetylsalicylic acid, to prevent/decreased up-regulation of 11β-HSD1 in human obese/metabolic syndrome adipose tissue.
|Alternate Journal||J. Clin. Endocrinol. Metab.|
|Grant List||CAF/11/13 / / Chief Scientist Office / United Kingdom |
WT083184 / / Wellcome Trust / United Kingdom