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Prepublished online as a Blood First Edition Paper on April 10, 2003; DOI 10.1182/blood-2002-11-3437. This Article Full Text (PDF) All Versions of this Article: 2002-11-3437v1 102/3/1078    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Moreno, J. L Articles by Tondravi, M. Search for Related Content PubMed PubMed Citation Articles by Moreno, J. L Articles by Tondravi, M. Social Bookmarking                   What's this? Submitted November 13, 2002 Accepted March 26, 2003 IL-4 suppresses both osteoclast development and mature osteoclast function by a STAT6-dependent mechanism: irreversible inhibition of the differentiation program activated by RANKL Jose L Moreno, Michele Kaczmareck, Achsah D Keegan, and Mehrdad Tondravi* Immunology, Jerome H. Holland Laboratory for the Biomedical Sciences, American Red Cross, Rockville, MD, USA; Hematopoiesis, Jerome H. Holland Laboratory for the Biomedical Sciences, American Red Cross, Rockville, MD, USA Immunology, Jerome H. Holland Laboratory for the Biomedical Sciences, American Red Cross, Rockville, MD, USA Hematopoiesis, Jerome H. Holland Laboratory for the Biomedical Sciences, American Red Cross, Rockville, MD, USA * Corresponding author; email: TondraviM{at}EXTRA.NIDDK.NIH.GOV. There have been numerous reports describing effects of IL-4 on bone biology. Previous studies, performed using complex co-culture systems, demonstrated effects of IL-4 on both osteoblasts and osteoclasts. To directly test the effect of IL-4 on osteoclasts, we took advantage of a simplified system using recombinant RANKL as the osteoclast differentiation factor. We analyzed the ability of IL-4 to directly regulate osteoclast differentiation and mature osteoclast function. We found that IL-4 inhibited the differentiation of osteoclasts from bone marrow precursors in an irreversible manner and also inhibited the resorptive capacity of mature osteoclasts. In the presence of IL-4 we detected the appearance of TRAP negative mutinucleated giant cells (MNG). Both IL-4 effects were dependent upon STAT6. We found that IL-4 suppresses RANK mRNA expression in the developing precursor cells. When RANK was ectopically expressed under the CMV promoter in RAW264.7 macrophages, IL-4 treatment did not inhibit osteoclast development. Furthermore, when osteoclastogenesis was induced independently of RANKL by using TNF, IL-4 inhibited osteoclast differentiation through a STAT6 dependent mechanism. These results suggest that IL-4 regulates osteoclast development by regulating gene expression including RANK. We propose that IL-4 irreversibly regulates the lineage commitment of precursor cells by regulating gene expression resulting in the suppression of osteoclast development and the generation of MNG as an alternative pathway of differentiation. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Yu, J. L. Moreno, J. P. Stains, and A. D. Keegan Complex Regulation of Tartrate-resistant Acid Phosphatase (TRAP) Expression by Interleukin 4 (IL-4): IL-4 INDIRECTLY SUPPRESSES RECEPTOR ACTIVATOR OF NF-{kappa}B LIGAND (RANKL)-MEDIATED TRAP EXPRESSION BUT MODESTLY INDUCES ITS EXPRESSION DIRECTLY J. Biol. 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