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MBC in Press, published online ahead of print October 8, 2008
Mol. Biol. Cell 10.1091/mbc.E07-02-0101

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Submitted on February 5, 2007
Revised on September 8, 2008
Accepted on September 26, 2008

Neonatal Fc Receptor Mediates Internalization of Fc in Transfected Human Endothelial Cells

Nancy A. Goebl,* Clifford M. Babbey,{dagger} Amita Datta-Mannan,* Derrick R. Witcher,{ddagger} Victor J. Wroblewski,* and Kenneth W. Dunn{dagger}

*Department of Drug Disposition Development/Commercialization, and {ddagger}Biotechnology Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285; {dagger}Department of Medicine, Division of Nephrology, Indiana University Medical Center, Indianapolis, IN 46202

Monitoring Editor: Sandra L. Schmid

The neonatal Fc receptor, FcRn mediates an endocytic salvage pathway that prevents degradation of IgG, thus contributing to the homeostasis of circulating IgG. Based upon the low affinity of IgG for FcRn at neutral pH, internalization of IgG by endothelial cells is generally believed to occur via fluid-phase endocytosis. To investigate the role of FcRn in IgG internalization, we used quantitative confocal microscopy to characterize internalization of fluorescent Fc molecules by HULEC-5A lung microvascular endothelia transfected with GFP fusion proteins of human or mouse FcRn. In these studies, cells transfected with FcRn accumulated significantly more intracellular Fc than untransfected cells. Internalization of FcRn-binding forms of Fc was proportional to FcRn expression level, was enriched relative to dextran internalization in proportion to FcRn expression level and was blocked by incubation with excess unlabeled Fc. As we were unable to detect either surface expression of FcRn or surface binding of Fc, these results suggest that FcRn-dependent internalization of Fc may occur through sequestration of Fc by FcRn in early endosomes. These studies indicate that FcRn-dependent internalization of IgG may be important not only in cells taking up IgG from an extracellular acidic space, but also in endothelial cells participating in homeostatic regulation of circulating IgG levels.

Address correspondence to: Kenneth W. Dunn (kwdunn{at}iupui.edu)




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