Interleukin-18 suppresses adiponectin expression in 3T3-L1 adipocytes via a novel signal transduction pathway involving ERK1/2-dependent NFATc4 phosphorylation.
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.
Chandrasekar
Bysani
B
Department of Veterans Affairs South Texas Veterans Health Care System, San Antonio, Texas 78229-4404, USA. chandraseka@uthscsa.edu
Patel
Devang N
DN
Mummidi
Srinivas
S
Kim
Jae-woo
JW
Clark
Robert A
RA
Valente
Anthony J
AJ
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism*; D052242:Adiponectin / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D017930:Genes, Reporter; D020382:Interleukin-18 / Q000502:physiology*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000502:physiology*
D052242:Adiponectin; D017931:DNA Primers; D020382:Interleukin-18; D050778:NFATC Transcription Factors; C467907:Nfatc4 protein, mouse; D034741:RNA, Small Interfering; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3