Department of Dermatology, Faculty of Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
J Invest Dermatol. 2011 Sep;131(9):1927-35. doi: 10.1038/jid.2011.135. Epub 2011 May 19.
CCL21 expression by lymphatic endothelial cells (LECs) is essential for migration of CCR7+ immune cells from skin to regional lymph nodes (LNs). We investigated the importance of mitogen-activated protein kinase (MAPK) signaling in CCL21 expression by ECs in vitro and in vivo. Normal human dermal lymphatic microvascular ECs (HMVEC-dLy) stimulated in vitro with oncostatin M (OSM) expressed high amounts of CCL21 mRNA. CCL21 protein expression by HMVEC-dLy was also markedly increased by OSM compared with unstimulated cultures. Marked phosphorylation of MAPK 44/42 was detected in HMVEC-dLy stimulated by OSM. CCL21 expression by HMVEC-dLy was blocked by a JAK inhibitor 1, JAK3 inhibitor, and U0126 (a MAPK kinase inhibitor) in vitro, all of which blocked phosphorylation of MAPK 44/42. In addition, injection of U0126 into murine skin significantly decreased CCL21 mRNA and protein expression. Moreover, injection of U0126 before sensitization decreased migration of dendritic cells to draining LNs and decreased contact hypersensitivity responses. In summary, these results suggest that the MAPK pathway is important for CCL21 expression by LECs in vitro and in vivo. Blocking MAPK signaling within skin may offer a novel approach to treatment of inflammatory skin diseases.
CCL21 由淋巴管内皮细胞 (LEC) 表达，对于 CCR7+免疫细胞从皮肤迁移到局部淋巴结 (LN) 是必需的。我们研究了丝裂原活化蛋白激酶 (MAPK) 信号通路在体外和体内 ECs 中 CCL21 表达的重要性。体外用 Oncostatin M (OSM) 刺激正常人皮肤淋巴微血管内皮细胞 (HMVEC-dLy) 可表达大量 CCL21 mRNA。与未刺激的培养物相比，OSM 还显著增加了 HMVEC-dLy 中 CCL21 蛋白的表达。在 OSM 刺激的 HMVEC-dLy 中检测到 MAPK 44/42 的明显磷酸化。在体外，JAK 抑制剂 1、JAK3 抑制剂和 U0126（MAPK 激酶抑制剂）阻断了 HMVEC-dLy 中 CCL21 的表达，所有这些抑制剂均阻断了 MAPK 44/42 的磷酸化。此外，向小鼠皮肤注射 U0126 可显著降低 CCL21 mRNA 和蛋白的表达。此外，在致敏前注射 U0126 可减少树突状细胞向引流淋巴结的迁移，并减少接触性超敏反应。总之，这些结果表明 MAPK 通路对于体外和体内 LEC 中 CCL21 的表达很重要。阻断皮肤内的 MAPK 信号可能为治疗炎症性皮肤病提供一种新方法。
