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Published online before print September 12, 2007

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0107058

Received for publication January 23, 2007.
Revised August 10, 2007.
Accepted for publication August 13, 2007.

Article

IL-4 promotes the formation of multinucleated giant cells from macrophage precursors by a STAT6-dependent, homotypic mechanism: contribution of E-cadherin

Jose L. Moreno ^*, Irina Mikhailenko , Mehrdad M. Tondravi , and Achsah D. Keegan ^||@

*Department of Orthopedics, Center for Vascular and Inflammatory Disease, Program in Oncology, Marlene and Stewart Greenebaum Cancer Center, and ^||Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA; and Department of Hematopoiesis, Jerome H. Holland Laboratory for the Biomedical Sciences, American Red Cross, Rockville, Maryland, USA

^@ To whom correspondence should be addressed. E-mail: akeegan{at}som.umaryland.edu.

	Abstract

Multinucleated giant cells (MNG) are central players in the inflammatory response to foreign materials and in adverse responses to implants. IL-4 promotes the formation of MNG from bone marrow-derived precursors in vitro and participates in the development of the foreign body reaction in vivo. Therefore, we investigated the mechanism by which IL-4 promotes formation of MNG and engulfment of foreign bodies. We found that generation of MNG cells by IL-4 was dependent on cell density and expression of STAT6; macrophages derived from STAT6^-/- mice were unable to form MNG in response to IL-4. No soluble factors including CCL2 or supernatants from IL-4-treated macrophages compensated for the lack of MNG cells in STAT6^-/- cultures. We found that IL-4 must remain present during the full differentiation process and that STAT6^+/+ macrophage precursors retained their ability to differentiate into MNG over time. These MNG were able to internalize large particles efficiently, and the mononuclear STAT6^-/- macrophages were unable to do so. Furthermore, we found that IL-4 induced expression of E-cadherin and dendritic cell-specific transmembrane protein in a STAT6-dependent manner. E-cadherin expression was critical for the formation of MNG cells by IL-4; an anti-E-cadherin antibody prevented the formation of large MNG. In addition, we found that STAT6^-/- progenitors failed to fuse with STAT6^+/+, revealing the need for a homotypic interaction. Thus, IL-4 promotes the formation of MNG in a STAT6-dependent manner by regulating cell surface expression of E-cadherin, leading to homotypic cell fusion and the incorporation of large foreign bodies.

Key Words: inflammation • macrophage • phagocytosis • fusion • DC-STAMP • cell differentiation

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