CXCR2 ligands and G-CSF mediate PKCα-induced intraepidermal inflammation

被引:63
作者
Cataisson, Christophe
Pearson, Andrea J.
Tsien, Margaret Z.
Mascia, Francesca
Gao, Ji-Liang
Pastore, Saveria
Yuspa, Stuart H.
机构
[1] NCI, Cellular Carcinogenesis & Tumor Promot Lab, Canc Res Ctr, Bethesda, MD 20892 USA
[2] NIAID, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA
[3] Ist Dermopat Immacolata, Rome, Italy
关键词
D O I
10.1172/JCI27514
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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.
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页码:2757 / 2766
页数:10
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