Functional caspase-1 is required for langerhans cell migration and optimal contact sensitization in mice
Functional caspase-1 is required for langerhans cell migration and optimal contact sensitization in mice
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DOI：
10.4049/jimmunol.166.6.3672
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发表时间：
2001-03-15
影响因子：
4.4
通讯作者：
Groves, RW
中科院分区：
文献类型：
--
作者：
Antonopoulos, H;Cumberbatch, M;Groves, RW
朗格汉斯细胞（LC）从表皮迁移到引流淋巴结是皮肤免疫应答的关键第一步。TNF-α和IL-1 β都是控制这一过程的重要信号，但半胱天冬酶-1对LL-1 α加工的潜在调节作用尚不清楚。在野生型（WT）小鼠中，应用接触性过敏原2，4-二硝基氟苯和恶唑酮导致表皮LC数量显著减少，但在半胱天冬酶-1缺陷型小鼠中未观察到这种减少。此外，尽管皮内注射TNF-α（50 ng）诱导WT小鼠表皮LC迁移，但这种细胞因子未能诱导caspase-1缺陷小鼠LC迁移。皮内IL-1 β）（50 ng）在WT和半胱天冬酶-1缺陷型小鼠中引起表皮LC数量的类似减少，表明给予适当的信号，半胱天冬酶-1缺陷型表皮LC能够迁移。接触性超敏反应，2，4-二硝基氟苯和恶唑酮抑制caspase-1缺陷小鼠，表明LC迁移缺陷的功能后果。在器官培养中，胱天蛋白酶-1抑制剂Ac-YVAD-cmk，而不是对照肽，有效地抑制了表皮LC迁移，发生在这个系统中，并减少自发迁移的LC中观察到的皮肤来源于胱天蛋白酶-1缺陷小鼠。此外，Ac-YVAD-cmk在应用接触致敏剂之前应用于BALB/c小鼠皮肤抑制LC迁移和体内接触超敏反应。两者合计，这些数据表明，半胱天冬酶-1可能发挥了核心作用，在LC迁移的调节，并建议，这种酶的活性是服从控制的特异性抑制剂在体内和体外。
Langerhans cell (LC) migration from epidermis to draining lymph node is a critical first step in cutaneous immune responses. Both TNF-alpha and IL-1 beta are important signals governing this process, but the potential regulatory role of LL-l alpha processing by caspase-1 is unknown, In wild-type (WT) mice, application of the contact allergens 2,4-dinitrofluorobenzine and oxazolone lead to a marked reduction in epidermal LC numbers, but in caspase-1-deficient mice this reduction was not observed. Moreover, although intradermal injection of TNF-alpha (50 ng) induced epidermal LC migration in WT mice, this cytokine failed to induce LC migration in caspase-1-deficient mice. Intradermal IL-1 beta) (50 ng) caused a similar reduction in epidermal LC numbers in both WT and caspase-1-deficient mice, indicating that, given an appropriate signal, caspase-1-deficient epidermal LC are capable of migration. Contact hypersensitivity to both 2,4-dinitrofluorobenzine and oxazolone was inhibited in caspase-1-deficient mice, indicating a functional consequence of the LC migration defect. In organ culture the caspase-1 inhibitor Ac-YVAD-cmk, but not control peptide, potently inhibited the epidermal LC migration that occurs in this system, and reduced spontaneous migration of LC was observed in skin derived from caspase-1-deficient mice. Moreover, Ac-YVAD-cmk applied to BALB/c mouse skin before application of contact sensitizers inhibited LC migration and contact hypersensitivity in vivo. Taken together, these data indicate that Caspase-1 may play a central role in the regulation of LC migration and suggest that the activity of this enzyme is amenable to control by specific inhibitors both in vivo and in vitro.