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Oncostatin M Enhances CCL21 Expression by Microvascular Endothelial Cells and Increases the Efficiency of Dendritic Cell Trafficking to Lymph Nodes¹

Dermatology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892

CCL21, a lymphatic endothelial cell (LEC)-derived chemokine, and its receptor CCR7 regulate dendritic cell (DC) trafficking to lymph nodes (LN), but it is unclear how CCL21 expression is regulated. Oncostatin M (OSM) is an IL-6-like cytokine synthesized by activated DC and other leukocytes. In vitro, OSM (but not TNF-) stimulated CCL21 mRNA and protein expression by human dermal microvascular EC (DMEC) in an ERK1/2-dependent fashion. Conditioned medium from OSM-treated DMEC stimulated CCL21-dependent chemotaxis of mouse bone marrow-derived DC (BMDC). Cultured BMDC expressed OSM, which was increased with the addition of LPS. Topical application of the contact-sensitizing hapten, trinitrochlorobenzene, resulted in enhanced OSM expression in the skin, whereas cutaneous injection of TNF- did not. Injection of OSM into the footpad increased CCL21 mRNA expression in the draining LN by 10-fold and in mouse skin by 4-fold without increasing CCR7 mRNA. In vitro, OSM increased the permeability of DMEC and lung microvascular EC monolayers to FITC-dextran beads, and, in vivo, it enhanced accumulation of Evans blue dye in draining LN by 3-fold (p = 0.0291). Of note, OSM increased trafficking of BMDC injected in footpads to draining LN by 2-fold (p = 0.016). In summary, OSM up-regulates CCL21 expression in skin and draining regional LN. We propose that OSM is a regulator of CCL21 expression and endothelial permeability in skin, contributing to efficient migration of DC to regional LN.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. S.H.J. was supported by the National Institutes of Health Clinical Training Research Program.

² Current address: Department of Dermatology, Faculty of Medicine, University of Tokyo, Tokyo 113-8655, Japan.

³ M.S., L.F., and A.R.C. contributed equally to the execution of the study.

⁴ Current address: Departments of Dermatology and Molecular Microbiology and Immunology, Oregon Health & Science University and Dermatology Service, Veterans Affairs Medical Center, 3710 Southwest U.S. Veterans Hospital Road, R&D 55, Portland, OR 97239.

⁵ Address correspondence and reprint requests to Dr. Sam T. Hwang, Senior Investigator, 10 Center Drive, Room 12N258, Bethesda, MD, 20852. E-mail address: hwangs{at}mail.nih.gov

⁶ Abbreviations used in this paper: DC, dendritic cell; LN, lymph node; EC, endothelial cell; LEC, lymphatic EC; BVEC, blood vascular EC; DMEC, dermal microvascular EC; LYVE-1, lymphatic vascular EC-1; VEGF, vascular endothelial growth factor; OSM, oncostatin M; HDF, human dermal fibroblast; LMEC, lung microvascular EC; BMDC, bone marrow-derived DC; m, murine; for, forward; rev, reverse; RT, room temperature; rm, recombinant murine; rh, recombinant human; hOSM, human OSM; TNCB, trinitrochlorobenzene.

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