Tumor-promoting role of TGF1 signaling in ultraviolet B-induced skin carcinogenesis is associated with cutaneous inflammation and lymph node migration of dermal dendritic cells
Tumor-promoting role of TGF1 signaling in ultraviolet B-induced skin carcinogenesis is associated with cutaneous inflammation and lymph node migration of dermal dendritic cells
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DOI：
10.1093/carcin/bgt486
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发表时间：
2014-04-01
期刊：
影响因子：
4.7
通讯作者：
Glick, Adam B.
中科院分区：
文献类型：
--
作者：
Ravindran, Anand;Mohammed, Javed;Glick, Adam B.
转化生长因子 β 1 (TGF β 1) 是皮肤中的一种多效细胞因子，在化学诱导的皮肤癌发生中既可以作为肿瘤促进剂，也可以作为抑制剂，但其在紫外线 B (UVB) 癌发生中的功能尚不清楚。用激活素样激酶 5 (ALK5) 抑制剂 SB431542 治疗 SKH1 无毛小鼠，阻断 UVB 诱导的皮肤 TGF beta 1 信号激活，抑制皮肤肿瘤形成，但不会改变肿瘤大小或肿瘤细胞增殖。与对照小鼠相比，30周后SB治疗小鼠中出现的肿瘤中IFNγ(+)肿瘤浸润淋巴细胞的百分比显着降低。 SB431542 可阻断 UVB 诱导的急性和慢性皮肤炎症以及皮肤引流淋巴结 (SDLN) 和皮肤中的 T 细胞活化，但不会改变 UVB 诱导的表皮增殖。我们测试了 SB431542 对皮肤树突状细胞 (DC) 群体迁移的影响，因为 DC 是 T 细胞激活和皮肤炎症的关键介质。 SB431542 阻断 (i) UVB 诱导的真皮 DC (dDC) 中的 Smad2 磷酸化和 (ii) CD103(+) CD207(+) 和 CD207(-) 皮肤 DC 子集的 SDLN 和耳外植体迁移，但不影响朗格汉斯细胞的基础或 UV 诱导的迁移。在CD11c(+)细胞中表达显性失活TGFβII型受体的小鼠，在UVB照射后，CD103(+)、CD207(+)和CD207-DC亚群的基础和UVB诱导的SDLN迁移减少，并且CD86(高)dDC的百分比减少。总之，这些表明 TGF beta 1 信号传导在 UVB 诱导的皮肤癌发生中具有肿瘤促进作用，并且这部分是通过其在 UVB 诱导的 dDC 迁移和皮肤炎症中的作用介导的。
Transforming growth factor beta 1 (TGF beta 1) is a pleiotropic cytokine in the skin that can function both as a tumor promoter and suppressor in chemically induced skin carcinogenesis, but the function in ultraviolet B (UVB) carcinogenesis is not well understood. Treatment of SKH1 hairless mice with the activin-like kinase 5 (ALK5) inhibitor SB431542 to block UVB-induced activation of cutaneous TGF beta 1 signaling suppressed skin tumor formation but did not alter tumor size or tumor cell proliferation. Tumors that arose in SB-treated mice after 30 weeks had significantly reduced percentage of IFN gamma(+) tumor-infiltrating lymphocytes compared with control mice. SB431542 blocked acute and chronic UVB-induced skin inflammation and T-cell activation in the skin-draining lymph node (SDLN) and skin but did not alter UVB-induced epidermal proliferation. We tested the effect of SB431542 on migration of skin dendritic cell (DC) populations because DCs are critical mediators of T-cell activation and cutaneous inflammation. SB431542 blocked (i) UVB-induced Smad2 phosphorylation in dermal DC (dDC) and (ii) SDLN and ear explant migration of CD103(+) CD207(+) and CD207(-) skin DC subsets but did not affect basal or UV-induced migration of Langerhans cells. Mice expressing a dominant-negative TGF beta type II receptor in CD11c(+) cells had reduced basal and UVB-induced SDLN migration of CD103(+) CD207(+) and CD207-DC subsets and a reduced percentage of CD86(high) dDC following UVB irradiation. Together, these suggest that TGF beta 1 signaling has a tumor-promoting role in UVB-induced skin carcinogenesis and this is mediated in part through its role in UVB-induced migration of dDC and cutaneous inflammation.