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Published online before print September 12, 2007

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(Journal of Leukocyte Biology. 2007;82:1542-1553.)
© 2007 by Society for Leukocyte Biology

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^,,||,1

^* 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

¹Correspondence: Center for Vascular and Inflammatory Diseases, University of Maryland, Baltimore, 800 W. Baltimore St., Baltimore, MD 21201, USA. E-mail: akeegan{at}som.umaryland.edu

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 • phagocytosis • fusion • DC-STAMP • cell differentiation