Interleukin-3 and granulocyte-macrophage colony-stimulating factor inhibits tumor necrosis factor (TNF)-alpha-induced osteoclast differentiation by down-regulation of expression of TNF receptors 1 and 2.
Osteoclasts, the multinucleated cells that resorb bone, differentiate from hemopoietic precursors of monocyte/macrophage lineage, which also give rise to macrophages or dendritic cells. In this study we investigated the mechanism by which interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) inhibit tumor necrosis factor (TNF)-alpha-induced osteoclast differentiation in mouse osteoclast precursors. We show here that both IL-3 and GM-CSF potently inhibits TNF-alpha-induced osteoclast differentiation by direct action on osteoclast precursors. The inhibitory effect of IL-3 and GM-CSF on osteoclast differentiation was completely neutralized by anti-IL-3 and anti-GM-CSF antibodies, respectively. In addition, the inhibitory effect of IL-3 and GM-CSF on TNF-alpha-induced osteoclast differentiation was irreversible. In osteoclast precursors, IL-3 and GM-CSF inhibited c-Fms expression post-transcriptionally. Interestingly, IL-3 and GM-CSF down-regulated both mRNA and surface expression of TNF receptor 1 (TNFR1) and TNFR2. Furthermore, cells in the presence of IL-3 and GM-CSF showed high expression of macrophage antigen CD11b, and low expression of dendritic cells antigen CD11c and prolong exposure of osteoclast precursors to GM-CSF increased the CD11c expression compare with IL-3. In summary, we provide the first evidence that IL-3 and GM-CSF block TNF-alpha-induced osteoclast differentiation by down-regulation of mRNA and surface expression of TNFR1 and TNFR2.
Yogesha
S D
SD
National Center for Cell Science, University of Pune Campus, Ganeshkhind Rd., Pune 411 007, India.
Khapli
Shruti M
SM
Wani
Mohan R
MR
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D015536:Down-Regulation; D005786:Gene Expression Regulation; D016236:Genes, fms; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D007377:Interleukin-3 / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics*; D013234:Stem Cells / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
D007377:Interleukin-3; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D016178:Granulocyte-Macrophage Colony-Stimulating Factor