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
Volume99
Issue1
PaginationE160-8
Date Published2014 Jan
ISSN1945-7197
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
Abstract

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="" kinase="" attenuated="" ccaat="" binding="" protein="" phosphorylation="" at="" thr235="" and="" il-1="" induction="" small="" interfering="" rna-mediated="" knockdown="" c="" nuclear="" factor="" or="" nf-="" also="" cytokine="" moreover="" by="" in="" sgbs="" cells="" was="" associated="" with="" localization="" chromatin="" immunoprecipitation="" experiments="" showed="" located="" to="" promoter="" human="" adipose="" tissue.="" treatment="" adipocyte="" fractions="" adipocytes="" metformin="" acetylsalicylic="" acid="" which="" target="" signaling="">

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.

DOI10.1210/jc.2013-1708
Alternate JournalJ. Clin. Endocrinol. Metab.
PubMed ID24243637
Grant ListCAF/11/13 / / Chief Scientist Office / United Kingdom
WT083184 / / Wellcome Trust / United Kingdom