Anti-inflammatory effects of the GABAB receptor agonist baclofen in allergic contact dermatitis
Anti-inflammatory effects of the GABAB receptor agonist baclofen in allergic contact dermatitis
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DOI：
10.1111/j.1600-0625.2010.01076.x
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发表时间：
2010-07-01
影响因子：
3.6
通讯作者：
Boehncke, Wolf-Henning
中科院分区：
文献类型：
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作者：
Duthey, Beatrice;Huebner, Anita;Boehncke, Wolf-Henning
γ氨基丁酸B （GABA(B)）受体是一种参与突触传递的G蛋白偶联受体（GPCR）。最近的数据表明，它也在免疫细胞上表达，以及趋化因子受体，这也是gpcr。由于gpcr可以经历异源脱敏，我们研究了巴氯芬（一种GABA(B)受体选择性激动剂）干扰促炎趋化因子受体功能的能力，已知促炎趋化因子受体在皮肤炎症中上调。在体外，巴氯芬以剂量依赖性的方式降低人外周血单个核细胞对CCL2、CCL5、CXCL10、CXCL2和CX3CL1的趋化性。蛋白激酶C抑制剂calphostin C和G0 6976可以逆转这种效应，这表明钙依赖性和非依赖性蛋白激酶C都参与了巴氯芬诱导的趋化因子受体的抑制。在C57BL/6小鼠接触性超敏反应的体内模型中，腹腔注射巴氯芬可显著缓解炎症症状，并可促进皮肤中中性粒细胞、单核细胞和淋巴细胞的募集。本研究揭示了GABA(B)受体在炎症中的新作用，使其成为治疗炎症性皮肤病的潜在新靶点。
The gamma amino butyric acid B (GABA(B)) receptor is a G protein-coupled receptor (GPCR) involved in synaptic transmission. Recent data indicate it to be also expressed on immune cells, along with chemokine receptors, which are also GPCRs. As GPCRs can undergo heterologous desensitization, we have examined the ability of baclofen, a GABA(B) receptor selective agonist, to interfere with the function of pro-inflammatory chemokine receptors known to be upregulated in cutaneous inflammation. In vitro, baclofen reduces chemotaxis of human peripheral blood mononuclear cells towards CCL2, CCL5, CXCL10, CXCL2 and CX3CL1 in a dose-dependant manner. Protein kinase C inhibitors calphostin C and G0 6976 could reverse this effect, pointing towards the involvement of both calcium-dependent and -independent protein kinase C in baclofen-induced inhibition of chemokine receptors. In an in vivo model of contact hypersensitivity in C57BL/6 mice, intraperitoneal injection of baclofen markedly alleviated signs of inflammation as well as recruitment of neutrophils, monocytes and lymphocytes into the skin. This study demonstrates a new role for the GABA(B) receptor in inflammation, making it a potential new therapeutic target to treat inflammatory skin diseases.