Irreversible inhibition of RANK expression as a possible mechanism for IL-3 inhibition of RANKL-induced osteoclastogenesis.
IL-3, a cytokine secreted by activated T lymphocytes, stimulates the proliferation, differentiation and survival of pluripotent hematopoietic stem cells. In this study, we investigated the mechanism of inhibitory action of IL-3 on osteoclast differentiation. We show here that IL-3 significantly inhibits receptor activator of NF-kappaB (RANK) ligand (RANKL)-induced activation of c-Jun N-terminal kinase (JNK). IL-3 down-regulates expression of c-Fos and nuclear factor of activated T cells (NFATc1) transcription factors. In addition, IL-3 down-regulates RANK expression posttranscriptionally in both purified osteoclast precursors and whole bone marrow cells. Furthermore, the inhibitory effect of IL-3 on RANK expression was irreversible. Interestingly, IL-3 inhibits in vivo RANK expression in mice. Thus, we provide the first evidence that IL-3 irreversibly inhibits RANK expression that results in inhibition of important signaling molecules induced by RANKL.
Khapli
Shruti M
SM
National Center for Cell Science, University of Pune Campus, Pune 411 007, India.
Tomar
Geetanjali B
GB
Barhanpurkar
Amruta P
AP
Gupta
Navita
N
Yogesha
S D
SD
Pote
Satish T
ST
Wani
Mohan R
MR
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002454:Cell Differentiation; D002478:Cells, Cultured; D007377:Interleukin-3 / Q000378:metabolism* / Q000494:pharmacology; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D051379:Mice; D050778:NFATC Transcription Factors / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism*; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000037:antagonists & inhibitors / Q000096:biosynthesis*
D007377:Interleukin-3; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D016760:Proto-Oncogene Proteins c-fos; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D048670:MAP Kinase Kinase 4