Receptor activator of nuclear factor-kappaB is induced by a rottlerin-sensitive and p38 MAP kinase-dependent pathway during monocyte differentiation

Hong Soon Kang; Eui Kyun Park; Kyung Hee Kim; Ju-Young Park; Je-Yong Choi; Hong-In Shin; Chang-Duk Jun; Shin-Sung Kang; Shin-Yoon Kim

Receptor activator of nuclear factor-kappaB is induced by a rottlerin-sensitive and p38 MAP kinase-dependent pathway during monocyte differentiation

Mol Cells. 2004 Jun 30;17(3):438-45.

Authors

Hong Soon Kang¹, Eui Kyun Park, Kyung Hee Kim, Ju-Young Park, Je-Yong Choi, Hong-In Shin, Chang-Duk Jun, Shin-Sung Kang, Shin-Yoon Kim

Affiliation

¹ Skeletal Diseases Genome Research Center, Kyungpook National University Hospital, Kyungpook National University, Daegu 700-412, Korea.

PMID: 15232218

Abstract

Receptor activator of nuclear factor-kappaB (RANK) plays a central role in the regulation of osteoclast differentiation and activation, but the mechanisms underlying its expression remain to be elucidated. In the present study we showed that expression of RANK was strongly induced by phorbol-12-myristate-13-acetate (PMA) during monocyte differentiation of U937 cells, and was enhanced by concomitant treatment with vitamin D3. Induction was dramatically inhibited by protein kinase C (PKC) inhibitors such as rottlerin and Gö6983, but not by Gö6976. Interestingly, rottlerin, a selective inhibitor of PKCdelta, reduced PMA-induced RANK expression while having no effect on CD11b expression. However overexpression of wild type PKCdelta, or a kinase-inactive mutant, did not affect PMA-induction of RANK, suggesting that rottlerin inhibits PMA-induced expression of RANK via a PKCdelta-independent mechanism. Rottlerin also inhibited PMA-induced phosphorylation of p38 mitogen-activated protein kinase (p38MAPK), and the p38 MAPK inhibitor SB203580 inhibited induction of RANK. Rottlerin and SB203580 also substantially reduced RANK mRNA expression in mouse BMM cells stimulated with macrophage colony stimulating factor (M-CSF). Together, these results demonstrate that expression of RANK is dependent upon a rottlerin-sensitive and p38MAPK-dependent pathway during monocyte differentiation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetophenones / pharmacology*
Animals
Benzopyrans / pharmacology*
CD11b Antigen / metabolism
Carbazoles / pharmacology
Cell Differentiation / physiology*
Cells, Cultured
Cholecalciferol / pharmacology
Enzyme Activation / drug effects
Enzyme Inhibitors / pharmacology
Glycoproteins / metabolism*
Imidazoles / pharmacology
Indoles
MAP Kinase Signaling System / drug effects
Macrophage Colony-Stimulating Factor / pharmacology
Maleimides
Mice
Mitogen-Activated Protein Kinases / antagonists & inhibitors
Mitogen-Activated Protein Kinases / metabolism*
Monocytes / cytology*
Monocytes / metabolism
Osteoprotegerin
Phorbol Esters / pharmacology
Phosphorylation / drug effects
Protein Kinase C / antagonists & inhibitors
Protein Kinase C / metabolism
Protein Kinase C-delta
Pyridines / pharmacology
Receptors, Cytoplasmic and Nuclear / metabolism*
Receptors, Tumor Necrosis Factor
p38 Mitogen-Activated Protein Kinases

Substances

2-(1-(3-dimethylaminopropyl)-5-methoxyindol-3-yl)-3-(1H-indol-3-yl)maleimide
Acetophenones
Benzopyrans
CD11b Antigen
Carbazoles
Enzyme Inhibitors
Glycoproteins
Imidazoles
Indoles
Maleimides
Osteoprotegerin
Phorbol Esters
Pyridines
Receptors, Cytoplasmic and Nuclear
Receptors, Tumor Necrosis Factor
Tnfrsf11b protein, mouse
Cholecalciferol
Macrophage Colony-Stimulating Factor
rottlerin
Prkcd protein, mouse
Protein Kinase C
Protein Kinase C-delta
Mitogen-Activated Protein Kinases
p38 Mitogen-Activated Protein Kinases
SB 203580