AMP-activated protein kinase inhibitor decreases prostaglandin F2α-stimulated             interleukin-6 synthesis through p38 MAP kinase in osteoblasts.
We previously showed that prostaglandin F(2α) (PGF(2α)) stimulates the synthesis of interleukin-6 (IL-6), a potent bone resorptive agent, in part via p44/p42 mitogen-activated protein (MAP) kinase and p38 MAP kinase but not stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) among the MAP kinase superfamily in osteoblast-like MC3T3-E1 cells. In the present study, we investigated the involvement of AMP-activated protein kinase (AMPK), an intracellular energy sensor, in PGF(2α)-stimulated IL-6 synthesis in MC3T3-E1 cells. PGF(2α) time-dependently induced the phosphorylation of the AMPK α-subunit. Compound C, an inhibitor of AMPK, dose-dependently suppressed PGF(2α)-stimulated IL-6 release. Compound C reduced the PGF(2α)-induced acetyl-CoA carboxylase phosphorylation. In addition, PGF(2α)-stimulated IL-6 release in human osteoblasts was also inhibited by compound C. The IL-6 mRNA expression induced by PGF(2α) was markedly reduced by compound C. Downregulation of the AMPK α1-subunit by short interfering RNA (siRNA) significantly suppressed the PGF(2α)-stimulated IL-6 release. PGF(2α)-induced phosphorylation of p38 MAP kinase was inhibited by compound C, which failed to affect the p44/p42 MAP kinase phosphorylation. These results strongly suggest that AMPK regulates PGF(2α)-stimulated IL-6 synthesis via p38 MAP kinase in osteoblasts.
Department of Orthopedic Surgery, Nagoya City University Graduate                     School of Medical Sciences, Nagoya 467-8601, Japan.
Akira
A
Kondo
Takanobu
T
Otsuka
Kenji
K
Kato
Hideo
H
Natsume
Gen
G
Kuroyanagi
Jun
J
Mizutani
Yoshiki
Y
Ito
Rie
R
Matsushima-Nishiwaki
Osamu
O
Kozawa
Haruhiko
H
Tokuda
D016475:3T3 Cells; D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000818:Animals; D015237:Dinoprost / Q000502:physiology*; D055785:Gene Knockdown Techniques; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D010006:Osteoblasts / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D015850:Interleukin-6; D021122:Protein Subunits; D011720:Pyrazoles; D011743:Pyrimidines; D034741:RNA, Small Interfering; C516138:dorsomorphin; D015237:Dinoprost; C548179:Prkaa1 protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase