Leading science, pioneering therapies
CRM Publications

Proinflammatory cytokine induction of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in human adipocytes is mediated by MEK, C/EBPβ, and NF-κB/RelA.

TitleProinflammatory cytokine induction of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in human adipocytes is mediated by MEK, C/EBPβ, and NF-κB/RelA.
Publication TypeJournal Article
Year of Publication2014
AuthorsEsteves CL, Kelly V, Breton A, Taylor AI, West CC, Donadeu FXavier, Péault B, Seckl JR, Chapman KE
JournalJ Clin Endocrinol Metab
Date Published2014 Jan
Keywords11-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 JournalJ. Clin. Endocrinol. Metab.
PubMed ID24243637
Grant ListCAF/11/13 / / Chief Scientist Office / United Kingdom
WT083184 / / Wellcome Trust / United Kingdom