Differential regulation of neutrophil-activating chemokines by IL-6 and its soluble receptor isoforms
Differential regulation of neutrophil-activating chemokines by IL-6 and its soluble receptor isoforms
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DOI：
10.4049/jimmunol.172.9.5676
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发表时间：
2004-05-01
影响因子：
4.4
通讯作者：
Jones, SA
中科院分区：
文献类型：
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作者：
McLoughlin, RM;Hurst, SM;Jones, SA
白细胞介素-6信号通过其可溶性受体（sIL-6 R）差异调节炎性趋化因子表达和白细胞凋亡，以协调从中性粒细胞向单核细胞浸润的转变。然而，sIL-6 R活性可能在体内受到两种sIL-6 R同种型的影响，这两种同种型是由于同源IL-6 R的差异mRNA剪接（DS）或蛋白水解裂解（PC）而释放的（称为DS-和PC-sIL-6 R）。使用人腹膜间皮细胞和腹膜炎症的小鼠模型，在这项工作中描述的研究比较了两种亚型调节中性粒细胞募集的能力。在这方面，DS-和PC-sIL-6 R的活性相当;然而，这些研究强调，IL-6反式信号转导差异控制嗜中性粒细胞活化CXC趋化因子的表达。在体外，用IL-6与DS-sIL-6 R或PC-sIL-6 R组合刺激间皮瘤细胞显示没有诱导CXC趋化因子配体（CXCL）1（GRO α）和CXCL 8（IL-8），而两种同种型均增强CXCL 5（ENA-78）和CXCL 6（粒细胞趋化蛋白-2）表达。此外，当与IL-6复合时，两种亚型都特异性抑制IL-1 β诱导的CXCL 8分泌。这些发现在体内得到证实，在IL-6缺陷（IL-6（-/-））小鼠中诱导腹膜炎症导致角化细胞衍生的趋化因子和巨噬细胞炎性蛋白-2（CXCL 1和CXCL 8的鼠等效物）水平升高，但LPS诱导的CXC趋化因子（CXCL 5的鼠等效物）表达降低。用IL-6及其可溶性受体亚型重建IL-6（-/-）小鼠中的IL-6信号传导纠正了这种趋化因子失衡并抑制了总体中性粒细胞浸润。这些数据证实，sIL-6 R介导的信号主要限制中性粒细胞流入;然而，诱导CXCL 5和CXCL 6可能调节其他中性粒细胞反应。
Interleukin-6 signaling via its soluble receptor (sIL-6R) differentially regulates inflammatory chemokine expression and leukocyte apoptosis to coordinate transition from neutrophil to mononuclear cell infiltration. sIL-6R activities may, however, be influenced in vivo by the occurrence of two sIL-6R isoforms that are released as a consequence of differential mRNA splicing (DS) or proteolytic cleavage (PC) of the cognate IL-6R (termed DS- and PC-sIL-6R). Using human peritoneal mesothelial cells and a murine model of peritoneal inflammation, studies described in this work have compared the ability of both isoforms to regulate neutrophil recruitment. In this respect, DS- and PC-sIL-6R were comparable in their activities; however, these studies emphasized that IL-6 trans signaling differentially controls neutrophil-activating CXC chemokine expression. In vitro, stimulation of mesothelial cells with IL-6 in combination with either DS-sIL-6R or PC-sIL-6R showed no induction of CXC chemokine ligand (CXCL)1 (GROalpha) and CXCL8 (IL-8), whereas both isoforms enhanced CXCL5 (ENA-78) and CXCL6 (granulocyte chemotactic protein-2) expression. Moreover, when complexed with IL-6, both isoforms specifically inhibited the IL-1beta-induced secretion of CXCL8. These findings were paralleled in vivo, in which induction of peritoneal inflammation in IL-6-deficient (IL-6(-/-)) mice resulted in enhanced keratinocyte-derived chemokine and macrophage-inflammatory protein-2 (the murine equivalent of CXCL1 and CXCL8) levels, but reduced LPS-induced CXC chemokine (the murine equivalent of CXCL5) expression. Reconstitution of IL-6 signaling in IL-6(-/-) mice with IL-6 and its soluble receptor isoforms corrected this chemokine imbalance and suppressed overall neutrophil infiltration. These data confirm that sIL-6R-mediated signaling primarily limits neutrophil influx; however, induction of CXCL5 and CXCL6 may regulate other neutrophil responses.