A novel inflammatory pathway involved in leukocyte recruitment: role for the kinin B1 receptor and the chemokine CXCL5.
A novel inflammatory pathway involved in leukocyte recruitment: role for the kinin B1 receptor and the chemokine CXCL5.
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DOI：
10.4049/jimmunol.179.7.4849
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发表时间：
2007-10-01
期刊：
影响因子：
--
通讯作者：
Ahluwalia A
中科院分区：
文献类型：
--
作者：
Duchene J;Lecomte F;Ahmed S;Cayla C;Pesquero J;Bader M;Perretti M;Ahluwalia A
激动素B1受体是一种诱导性受体，不是正常表达的，而是在炎症刺激下诱导的，在中性粒细胞募集，特别是对细胞因子白介素1β(IL-1β)的反应中发挥着重要作用。然而，这一反应涉及的确切机制尚不清楚。本研究的目的是剖析其中的分子机制，特别是确定特定的ELR-CXCL趋化因子(特异性中性粒细胞趋化因子)是否在其中起作用。在活体显微镜下，我们证明了IL-1β诱导野生型(WT)小鼠肠系膜小静脉的白细胞滚动、黏附和迁移，并伴随着B1受体基因表达的增加，在B1受体敲除小鼠(B1KO)中显著减弱(>；80%)。与WT小鼠相比，B1KO小鼠的这种作用与选择性下调IL-1β诱导的CXCL5mRNA和蛋白表达有关。此外，选择性中和CXCL5抗体可显著抑制IL-1β处理的WT小鼠的白细胞迁移。最后，人内皮细胞经IL-1β处理后，B1受体及其同源物(hCXCL5和hCXCL6)的基因表达增强。当用B1受体拮抗剂DES-Arg9[Leu]8BK处理细胞时，这一反应被抑制约50%，而B1受体激动剂DES-Arg9-BK处理后，hCXCL5和hCXCL6mRNA的表达呈浓度依赖性增加。这项研究揭示了以激动素B1受体激活CXCL5为中心的促炎通路，导致白细胞转运，并强调B1受体是炎症性疾病治疗的潜在靶点。
The kinin B1 receptor is an inducible receptor not normally expressed but induced by inflammatory stimuli and plays a major role in neutrophil recruitment, particularly in response to the cytokine interleukin-1β (IL-1β). However, the exact mechanism involved in this response is unclear. The aim of this study was to dissect the molecular mechanism involved, in particular to determine whether specific ELR-CXCL chemokines (specific neutrophil chemoattractants) played a role. Using intravital microscopy, we demonstrated that IL-1 β induced leukocyte rolling, adherence and emigration in mesenteric venules of wild type (WT) mice, associated with an increase of B1 receptor mRNA expression, was substantially attenuated (>80%) in B1 receptor knockout mice (B1KO). This effect in B1KO mice was correlated with a selective down regulation of IL-1β-induced CXCL5 mRNA and protein expression compared to WT mice. Furthermore a selective neutralizing CXCL5 antibody caused profound suppression of leukocyte emigration in IL-1β treated WT mice. Finally, treatment of human endothelial cells with IL-1β enhanced mRNA expression of B1 receptor and the human CXCL5 homologues (hCXCL5 and hCXCL6). This response was suppressed by ~50% when cells were pretreated with the B1 receptor antagonist des-Arg9[Leu]8BK whilst treatment with des-Arg9-BK, the B1 receptor agonist, caused a concentration-dependent increase in hCXCL5 and hCXCL6 mRNA expression. This study unveils a pro-inflammatory pathway centred on kinin B1 receptor activation of CXCL5 leading to leukocyte trafficking, and highlights the B1 receptor as a potential target in the therapeutics of inflammatory disease.
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影响因子：
5.3
作者：
Ferreira, J;Beirith, A;Calixto, JB
通讯作者：
Calixto, JB
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6.5
作者：
Goebeler, M;Yoshimura, T;Gillitzer, R
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影响因子：
3.2
作者：
McIntyre, TM;Prescott, SM;Zimmerman, GA
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Zimmerman, GA
影响因子：
5.5
作者：
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通讯作者：
Figueroa, C. D.
影响因子：
20.1
作者：
Madorin, WS;Rui, T;Kvietys, PR
通讯作者：
Kvietys, PR