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

@article{citeulike:3064378, 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.}, address = {Department of Veterans Affairs South Texas Veterans Health Care System, San Antonio, Texas 78229-4404, USA. chandraseka@uthscsa.edu}, author = {Chandrasekar, B. and Patel, D. N. and Mummidi, S. and Kim, J. W. and Clark, R. A. and Valente, A. J.}, citeulike-article-id = {3064378}, citeulike-linkout-0 = {http://dx.doi.org/10.1074/jbc.M708142200}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/18086672}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=18086672}, day = {15}, doi = {10.1074/jbc.M708142200}, issn = {0021-9258}, journal = {The Journal of biological chemistry}, keywords = {adiponectin, erk, il-18}, month = {February}, number = {7}, pages = {4200--4209}, posted-at = {2008-07-31 01:29:59}, priority = {2}, title = {Interleukin-18 suppresses adiponectin expression in 3T3-L1 adipocytes via a novel signal transduction pathway involving ERK1/2-dependent NFATc4 phosphorylation.}, url = {http://dx.doi.org/10.1074/jbc.M708142200}, volume = {283}, year = {2008} }

TY - JOUR ID - citeulike:3064378 L3 - citeulike-article-id:3064378 N2 - 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. IS - 7 JF - The Journal of biological chemistry SN - 0021-9258 AD - Department of Veterans Affairs South Texas Veterans Health Care System, San Antonio, Texas 78229-4404, USA. chandraseka@uthscsa.edu EP - 4209 TI - Interleukin-18 suppresses adiponectin expression in 3T3-L1 adipocytes via a novel signal transduction pathway involving ERK1/2-dependent NFATc4 phosphorylation. VL - 283 SP - 4200 KW - adiponectin KW - erk KW - il-18 AU - Chandrasekar, B AU - Patel, DN AU - Mummidi, S AU - Kim, JW AU - Clark, RA AU - Valente, AJ PY - 2008/02/15/ UR - http://dx.doi.org/10.1074/jbc.M708142200 ER -