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J. Biol. Chem., Vol. 280, Issue 12, 11759-11769, March 25, 2005

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Interleukin-3 and Granulocyte-Macrophage Colony-stimulating Factor Inhibits Tumor Necrosis Factor (TNF)--induced Osteoclast Differentiation by Down-regulation of Expression of TNF Receptors 1 and 2^*

S. D. Yogesha, Shruti M. Khapli, and Mohan R. Wani

From the National Center for Cell Science, University of Pune Campus, Ganeshkhind Rd., Pune 411 007, India

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)--induced osteoclast differentiation in mouse osteoclast precursors. We show here that both IL-3 and GM-CSF potently inhibits TNF--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--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--induced osteoclast differentiation by down-regulation of mRNA and surface expression of TNFR1 and TNFR2.

Received for publication, September 21, 2004 , and in revised form, January 10, 2005.

^* This work was supported in part by the Department of Biotechnology, Government of India. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipients of Senior Research Fellowships from the Council for Scientific and Industrial Research (New Delhi, India).

To whom correspondence should be addressed: Tel.: 91-20-256-90922; Fax: 91-20-256-92259; E-mail: mohanwani{at}nccs.res.in.

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