This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by McNally, A. K. Articles by Anderson, J. M. Search for Related Content PubMed PubMed Citation Articles by McNally, A. K. Articles by Anderson, J. M.

(American Journal of Pathology. 2003;163:1147-1156.)
© 2003 American Society for Investigative Pathology

Foreign Body-Type Multinucleated Giant Cell Formation Is Potently Induced by -Tocopherol and Prevented by the Diacylglycerol Kinase Inhibitor R59022

From the Institute of Pathology, Case Western Reserve University, Cleveland, Ohio

Multinucleated foreign body giant cells (FBGCs) form by monocyte-derived macrophage fusion on implanted biomedical devices and are believed to mediate oxidative damage to biomaterial surfaces. Our in vitro system of human macrophage culture and interleukin (IL)-4-induced FBGC formation was developed to study the macrophage fusion mechanism and the physiological significance of FBGCs on implanted biomaterials and at other sites of chronic inflammation. Here, we demonstrate that the antioxidant vitamin E (90% -tocopherol) moderately induces macrophage fusion and increases IL-4-induced FBGC formation. Moreover, purified -tocopherol, but not ß-, -, or -tocopherol, most remarkably induces macrophage fusion, leading to cultures of confluent FBGCs below normal plasma concentrations. This is not observed with the similar antioxidants probucol or Trolox, suggesting that the -tocopherol effects on FBGC formation are independent of its antioxidant activity. Consistent with the reported activation of diacylglycerol kinase by -tocopherol, the diacylglycerol kinase inhibitor R59022 completely abrogates FBGC formation. R59022 inhibition of IL-4-induced FBGC formation is reversed by -tocopherol, suggesting that FBGC formation involves diacylglycerol kinase activation. This study suggests a novel role for diacylglycerol kinase in the mechanism of macrophage fusion/FBGC formation at sites of chronic inflammation and reveals that the pleiotropic lipophilic compound, -tocopherol, is a highly potent macrophage fusion factor.

This article has been cited by other articles:

				S. Li, E. Kimura, R. Ng, B. M. Fall, L. Meuse, M. Reyes, J. A. Faulkner, and J. S. Chamberlain A highly functional mini-dystrophin/GFP fusion gene for cell and gene therapy studies of Duchenne muscular dystrophy Hum. Mol. Genet., May 15, 2006; 15(10): 1610 - 1622. [Abstract] [Full Text] [PDF]

				T. H. Barker, P. Framson, P. A. Puolakkainen, M. Reed, S. E. Funk, and E. H. Sage Matricellular Homologs in the Foreign Body Response: Hevin Suppresses Inflammation, but Hevin and SPARC Together Diminish Angiogenesis Am. J. Pathol., March 1, 2005; 166(3): 923 - 933. [Abstract] [Full Text] [PDF]

				P. Kempna, E. Reiter, M. Arock, A. Azzi, and J.-M. Zingg Inhibition of HMC-1 Mast Cell Proliferation by Vitamin E: INVOLVEMENT OF THE PROTEIN KINASE B PATHWAY J. Biol. Chem., December 3, 2004; 279(49): 50700 - 50709. [Abstract] [Full Text] [PDF]

				A. AZZI, R. GYSIN, P. KEMPNA, A. MUNTEANU, Y. NEGIS, L. VILLACORTA, T. VISARIUS, and J.-M. ZINGG Vitamin E Mediates Cell Signaling and Regulation of Gene Expression Ann. N.Y. Acad. Sci., December 1, 2004; 1031(1): 86 - 95. [Abstract] [Full Text] [PDF]