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Interleukin-18 suppresses adiponectin expression in 3T3-L1 adipocytes via a novel signal transduction pathway involving ERK1/2-dependent NFATc4 phosphorylation.

Authors
 Bysani Chandrasekar  ;  Devang N. Patel  ;  Srinivas Mummidi  ;  Jae-woo Kim  ;  Robert A. Clark  ;  Anthony J. Valente 
Citation
 Journal of Biological Chemistry, Vol.283(7) : 4200-4209, 2008 
Journal Title
 Journal of Biological Chemistry 
ISSN
 0021-9258 
Issue Date
2008
MeSH
3T3-L1 Cells ; Adipocytes/metabolism* ; Adiponectin/genetics ; Adiponectin/metabolism* ; Animals ; Base Sequence ; Chromatin Immunoprecipitation ; DNA Primers ; Enzyme-Linked Immunosorbent Assay ; Genes, Reporter ; Interleukin-18/physiology* ; Mice ; Mitogen-Activated Protein Kinase 1/metabolism* ; Mitogen-Activated Protein Kinase 3/metabolism* ; NFATC Transcription Factors/metabolism* ; Phosphorylation ; Promoter Regions, Genetic ; RNA, Small Interfering ; Signal Transduction/physiology*
Keywords
3T3-L1 Cells ; Adipocytes/metabolism* ; Adiponectin/genetics ; Adiponectin/metabolism* ; Animals ; Base Sequence ; Chromatin Immunoprecipitation ; DNA Primers ; Enzyme-Linked Immunosorbent Assay ; Genes, Reporter ; Interleukin-18/physiology* ; Mice ; Mitogen-Activated Protein Kinase 1/metabolism* ; Mitogen-Activated Protein Kinase 3/metabolism* ; NFATC Transcription Factors/metabolism* ; Phosphorylation ; Promoter Regions, Genetic ; RNA, Small Interfering ; Signal Transduction/physiology*
Abstract
An inverse correlation between the pro-inflammatory cytokine interleukin-18 and the anti-atherogenic adipokine adiponectin has been reported in the chronic pathological conditions obesity, insulin resistance, coronary artery disease, and metabolic syndrome. We investigated whether this relationship is coincidental or has a causal basis. Here we show that interleukin-18 (IL-18) suppresses adiponectin transcription, mRNA expression, and secretion by 3T3-L1 adipocytes. IL-18 suppresses adiponectin promoter-reporter activity, an effect reversed by deletion or mutation of the NFATc4 core DNA-binding site. IL-18 induces NFATc4 phosphorylation (Ser(676)), nuclear translocation, and in vivo DNA binding. IL-18 induces ERK1/2 phosphorylation and enzyme activity, and pretreatment with the MEK inhibitor U0126, ERK1/2 inhibitor PD98059, or small interference RNA targeted to ERK1/2 attenuates ERK1/2 activation and NFATc4 phosphorylation. Finally, inhibition of ERK1/2 or NFATc4 knockdown reverses IL-18-mediated adiponectin suppression. In contrast to its inhibitory effects on adiponectin expression, IL-18 potently stimulates PAI-1 secretion. These data demonstrate for the first time that IL-18 selectively suppresses adiponectin expression via ERK1/2-dependent NFATc4 activation and suggest that the inverse relationship observed between IL-18 and adiponectin in various chronic pathological conditions is causally related. Thus, targeting IL-18 expression may enhance adiponectin expression and mitigate disease progression.
Files in This Item:
T200800698.pdf Download
DOI
10.1074/jbc.M708142200
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Biochemistry and Molecular Biology (생화학-분자생물학교실) > 1. Journal Papers
Yonsei Authors
Kim, Jae Woo(김재우) ORCID logo https://orcid.org/0000-0001-5456-9495
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/106950
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