AICAR induces cyclooxygenase-2 expression through AMP-activated protein kinase-transforming growth factor-beta-activated kinase 1-p38 mitogen-activated protein kinase signaling pathway.
AMP-activated protein kinase (AMPK), a critical signaling molecule for regulating energy homeostasis, might bi-directionally regulate inflammation, and its action mechanism leading to inflammation is not fully understood. We utilized 5-aminoimidazole-4-carboxamide riboside (AICAR) as a pharmacological activator of AMPK to unveil the effects of and signaling cascades mediated by AMPK on cyclooxygenase (COX)-2 gene expression in rat aortic vascular smooth muscle cells (VSMCs), murine macrophage cell line (J774), and human umbilical vein endothelial cells (HUVECs). Biochemical approaches were further conducted to elucidate interactions among signaling molecules. We found that AICAR could induce COX-2 protein expression in the cell types tested. This event was mediated by COX-2 gene transcription, and abrogated by compound C and 5'-iodotubercidin, suggesting the essential role of AMPK in COX-2 induction. Pharmacological and biochemical studies indicated that p38 mitogen-activated protein kinase (MAPK) activation is the common downstream signal of AMPK in COX-2 expression in all three cell types. Furthermore, we also found that TAK1 is associated with AMPKalpha2, and this binding requires an interaction between the kinase domains of both molecules. Notably data of TAK1 phosphorylation indicate that the activating state is enhanced upon AMPK activation in vivo and in vitro. Our data for the first time prove a pivotal role of TAK1 in the AMPK signaling axis. Such interaction gives AMPK an additional pathway for regulating cellular functions. Via a downstream p38 MAPK signaling cascade, AMPK-dependent TAK1 activation leads to the expression of the inflammatory COX-2 gene in various cell types.
Chang
Mei-Ying
MY
Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan. sarachang26@yahoo.com.tw
Ho
Feng-Ming
FM
Wang
Jang-Shiun
JS
Kang
Hao-Cheng
HC
Chang
Yung
Y
Ye
Zhi-Xian
ZX
Lin
Wan-Wan
WW
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects; D011464:Epoprostenol / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects; D051381:Rats; D012265:Ribonucleotides / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000099151:MAP Kinase Kinase Kinase 7
D055372:AMP-Activated Protein Kinases; D000620:Aminoimidazole Carboxamide; D051546:Cyclooxygenase 2; D011464:Epoprostenol; D020930:MAP Kinase Kinase Kinases; D012265:Ribonucleotides; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7; C031143:AICA ribonucleotide