Protein kinase Cα-mediated chemotaxis of neutrophils requires NF-κB activity but is independent of TNFα signaling in mouse skin in vivo
Protein kinase Cα-mediated chemotaxis of neutrophils requires NF-κB activity but is independent of TNFα signaling in mouse skin in vivo
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DOI：
10.4049/jimmunol.174.3.1686
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发表时间：
2005-02-01
影响因子：
4.4
通讯作者：
Yuspa, SH
中科院分区：
文献类型：
--
作者：
Cataisson, C;Pearson, AJ;Yuspa, SH
蛋白激酶 C (PKC) 亚型是皮肤稳态的主要调节因子，并介导 12-O-十四烷酰佛波醇-13-乙酸酯 (TPA) 引起的炎症。我们之前曾报道过，在皮肤中过度表达 PKCα 的转基因小鼠在接受 TPA 局部治疗时表现出严重的表皮内中性粒细胞炎症和角质形成细胞凋亡。 PKCα 的激活会增加 K5-PKCα 角质形成细胞中 TNFα 的产生以及趋化因子（MIP-2、KC、S100A8/A9）、血管内皮生长因子和 GM-CSF 的转录。响应 PKCα 激活，NF-kappaB 易位至细胞核，这与 IkappaB 磷酸化和降解相关。防止 IkappaB 降解会减少炎症相关基因的表达和趋化剂的释放。为了确定 TNFα 是否介导 NF-κB 易位和随后的促炎因子表达，用 p75 TNFR 二聚体可溶形式（依那西普）全身治疗 K5-PKCα 小鼠，或与两种 TNFR 同种型缺陷的小鼠杂交，并在 TNFα 中和抗体存在的情况下培养角质形成细胞。体内治疗和TNFR缺乏不能阻止炎症，体外治疗不能阻止TPA后NF-kappaB核转位。这些结果共同表明 PKCa 作为皮肤细胞因子和趋化因子子集的调节剂，负责独立于 TNFα 的表皮内炎症。 PKCα 抑制可能对某些人类炎症性皮肤病具有治疗作用。
Protein kinase C (PKC) isoforms are major regulators of cutaneous homeostasis and mediate inflammation in response to 12-O-tetradecanoylphorbol-13-acetate (TPA). We have previously reported that transgenic mice overexpressing PKCalpha in the skin exhibit severe intraepidermal neutrophilic inflammation and keratinocyte apoptosis when treated topically with TPA. Activation of PKCalpha increases the production of TNFalpha and the transcription of chemotactic factors (MIP-2, KC, S100A8/A9), vascular endothelial growth factor, and GM-CSF in K5-PKCalpha keratinocytes. In response to PKCalpha activation, NF-kappaB translocates to the nucleus and this is associated with IkappaB phosphorylation and degradation. Preventing IkappaB degradation reduces both the expression of inflammation-associated genes and chemoattractant release. To determine whether TNFalpha mediated NF-kappaB translocation and subsequent expression of proinflammatory factors, K5-PKCalpha mice were treated systemically with a dimeric soluble form of p75 TNFR (etanercept) or crossed with mice deficient for both TNFR isoforms, and keratinocytes were cultured in the presence of TNFalpha-neutralizing Abs. The in vivo treatment and TNFR deficiency did not prevent inflammation, and the in vitro treatment did not prevent NF-kappaB nuclear translocation after TPA. Together these results implicate PKCa as a regulator of a subset of cutaneous cytokines and chemokines responsible for intraepidermal inflammation independent of TNFalpha. PKCalpha inhibition may have therapeutic benefit in some human inflammatory skin disorders.