Generation of inhibitory NFκB complexes and phosphorylated cAMP response element-binding protein correlates with the anti-inflammatory activity of complement protein C1q in human monocytes
Generation of inhibitory NFκB complexes and phosphorylated cAMP response element-binding protein correlates with the anti-inflammatory activity of complement protein C1q in human monocytes
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DOI：
10.1074/jbc.m605741200
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发表时间：
2007-03-09
影响因子：
4.8
通讯作者：
Tenner, Andrea J.
中科院分区：
文献类型：
--
作者：
Fraser, Deborah A.;Arora, Meenakshi;Tenner, Andrea J.
C1q与免疫系统的特定细胞的相互作用诱导活性，如增强单核细胞的吞噬作用和刺激中性粒细胞超氧化物的产生。与其他一些单核细胞激活剂不同，C1q本身并不诱导促炎细胞因子的产生，而是抑制脂多糖（LPS）刺激的某些促炎细胞因子的诱导，并诱导白细胞介素-10的表达。为了研究C1q影响基因表达的分子机制，我们评估了C1q对NF κ B家族转录因子和cAMP反应元件结合蛋白（CREB）激活的影响。C1q处理增加了新分离的人单核细胞的kappa B结合活性，以时间依赖性的方式通过电泳迁移转移试验进行评估。在抗体超移实验中，抗p50抗体超移了C1q诱导的NF κ B复合物，而抗p65抗体作用不大，提示C1q诱导了NF κ B p50p50同型二聚体的易位。这与LPS刺激的平行单核细胞培养中p65复合物的显性诱导形成对比。C1q处理还诱导cAMP反应元件（CRE）结合活性，如电泳迁移率转移试验所示，CREB磷酸化增加，并诱导CRE驱动基因表达。相比之下，在lps处理的单核细胞中未检测到CREB活化。这些结果表明，C1q可能通过触发抑制和/或竞争信号来调节炎症刺激（如LPS）反应中表达的细胞因子谱。由于C1q和其他防御胶原已被证明可以增强凋亡细胞的清除，这一调节途径可能有助于避免自身免疫和/或解决炎症。
The interaction of C1q with specific cells of the immune system induces activities, such as enhancement of phagocytosis in monocytes and stimulation of superoxide production in neutrophils. In contrast to some other monocyte activators, C1q itself does not induce pro-inflammatory cytokine production, but rather inhibits the lipopolysaccharide (LPS)-stimulated induction of certain pro-inflammatory cytokines and induces expression of interleukin-10. To investigate the molecular mechanism by which C1q exerts this effect on gene expression, the influence of C1q on the activation of transcription factors of the NF kappa B family and cAMP response element-binding protein (CREB) was assessed. C1q treatment increased kappa B binding activity in freshly isolated human monocytes in a time-dependent fashion as assessed by electrophoretic mobility shift assays. In antibody supershift experiments, anti-p50 antibody supershifted the C1q-induced NF kappa B complex, whereas anti-p65 antibody had little effect, suggesting that C1q induced the translocation of NF kappa B p50p50 homodimers. This is in contrast to the dominant induction of p65 containing complexes in parallel monocyte cultures stimulated with LPS. C1q treatment also induced cAMP response element (CRE)-binding activity as demonstrated by electrophoretic mobility shift assay, increased phosphorylation of CREB, and induction of CRE driven gene expression. In contrast, CREB activation was not detected in LPS-treated monocytes. These results suggest that C1q may modulate the cytokine profile expressed in response to inflammatory stimuli (e.g. LPS), by triggering inhibitory and/or competing signals. Because C1q and other defense collagens have been shown to enhance clearance of apoptotic cells, this regulatory pathway may be beneficial in avoiding autoimmunity and/or resolving inflammation.