Proinflammatory cytokine induction of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in human adipocytes is mediated by MEK, C/EBPβ, and NF-κB/RelA.
BACKGROUND
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.
Endocrinology Unit, University/British Heart Foundation Centre for Cardiovascular Science (C.L.E., V.K., A.I.T., C.C.W., B.P., J.R.S., K.E.C.), Centre for Regenerative Medicine (C.C.W., B.P.), The University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom; and Division of Developmental Biology (A.B., F.X.D.), The Roslin Institute, EH25 9RG, United Kingdom.
Cristina L
CL
Esteves
Val
V
Kelly
Amandine
A
Breton
Ashley I
AI
Taylor
Christopher C
CC
West
Francesc X
FX
Donadeu
Bruno
B
Péault
Jonathan R
JR
Seckl
Karen E
KE
Chapman
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000096:biosynthesis*; D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism; D000328:Adult; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000502:physiology*; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D005260:Female; D006801:Humans; D007223:Infant; D018836:Inflammation Mediators / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000502:physiology*; D051996:Transcription Factor RelA / Q000502:physiology; D055815:Young Adult
D022782:CCAAT-Enhancer-Binding Protein-beta; D016207:Cytokines; D018836:Inflammation Mediators; D016328:NF-kappa B; C498143:RELA protein, human; D051996:Transcription Factor RelA; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D048049:Extracellular Signal-Regulated MAP Kinases