CXCR2 ligands and G-CSF mediate PKCα-induced intraepidermal inflammation
CXCR2 ligands and G-CSF mediate PKCα-induced intraepidermal inflammation
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DOI：
10.1172/jci27514
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发表时间：
2006-10-01
影响因子：
15.9
通讯作者：
Yuspa, Stuart H.
中科院分区：
文献类型：
--
作者：
Cataisson, Christophe;Pearson, Andrea J.;Yuspa, Stuart H.
在表皮中过度表达PKC α的转基因小鼠（K5-PKC α小鼠）在局部12-O-十四烷酰佛波醇-13-乙酸酯（TPA）激活PKC α时表现出可诱导的严重表皮内嗜中性炎症和全身嗜中性粒细胞。这种可诱导的皮肤炎症模型用于定义可能具有临床相关性的皮肤炎症介质。皮肤PKCa的激活增加了小鼠血浆中趋化因子姜黄素诱导的中性粒细胞趋化因子（KC）和巨噬细胞炎性蛋白2（MIP-2）的产生。TPA处理培养的K5-PKC α角质形成细胞也通过NF-κ B依赖性途径释放KC和MIP-2进入培养上清液。MIP-2和KC介导中性粒细胞浸润到表皮中，因为这通过消融K5-PKCa小鼠中的CXCR 2或施用针对KC或MIP-2的中和抗体来防止。嗜中性粒细胞增多症是由PKC α介导的皮肤G-CSF释放到血浆中的上调引起的，不依赖于CXCR 2。这些反应可以通过局部使用PKC α选择性抑制剂来抑制。抑制PKCa也降低了培养的银屑病角质形成细胞中CXCL 8的基础和TNF-α或TPA诱导的表达，表明PKC α活性可能有助于银屑病炎症。因此，皮肤可以是具有局部和全身后果的循环因子的来源，并且这些因子、它们的受体以及可能的PKC α可以是抑制皮肤炎症的治疗靶点。
Transgenic mice overexpressing PKC alpha in the epidermis (K5-PKC alpha mice) exhibit an inducible severe intraepi-dermal neutrophilic inflammation and systemic neutrophilia when PKCa is activated by topical 12-O-tetradecanoylphorbol-13-acetate (TPA). This inducible model of cutaneous inflammation was used to define mediators of skin inflammation that may have clinical relevance. Activation of cutaneous PKCa increased the production of the chemotactic factors cytokine-induced neutrophil chemoattractant (KC) and macrophage inflammatory protein 2 (MIP-2) in murine plasma. TPA treatment of cultured K5-PKC alpha keratinocytes also released KC and MIP-2 into culture supernatants through an NF-kappa B-dependent pathway. MIP-2 and KC mediated the infiltration of neutrophils into the epidermis, since this was prevented by ablating CXCR2 in K5-PKCa mice or administering neutralizing antibodies against KC or MIP-2. The neutrophilia resulted from PKC alpha-mediated upregulation of cutaneous G-CSF released into the plasma independent of CXCR2. These responses could be inhibited by topical treatment with a PKC alpha-selective inhibitor. Inhibiting PKCa also reduced the basal and TNF-alpha- or TPA-induced expression of CXCL8 in cultured psoriatic keratinocytes, suggesting that PKC alpha activity may contribute to psoriatic inflammation. Thus, skin can be the source of circulating factors that have both local and systemic consequences, and these factors, their receptors, and possibly PKC alpha could be therapeutic targets for inhibition of cutaneous inflammation.