Inflammation is characterized by early influx of polymorphonuclear neutrophils (PMNs), followed by a second wave of monocyte recruitment. PMNs mediate monocyte recruitment via their release of heparin binding protein (HBP), which activates CCR2 (CC-chemokine receptor 2) on monocytes. However, the pathways for such signal transmission remain unknown. Accumulating evidences have highlighted the importance of leukocyte-endothelial cell interactions in the initiation of inflammation. In this study, an interesting finding is that HBP enhances the secretion of monocyte chemotactic protein 1(MCP-1), ligand of CCR2, from a third party, the endothelial cells (ECs). HBP-induced increase in MCP-1 production was demonstrated at the protein, mRNA and secretion levels. Exposure of ECs to HBP elicited rapid phosphorylation of FAK/PI3K/AKT and p38 MAPK/NF-κB signaling. MCP-1 levels were attenuated during the response to HBP stimulation by pretreatment with a FAK inhibitor (or siRNA), a PI3K inhibitor, an AKT inhibitor, a p38 inhibitor (or siRNA) and two NF-κB inhibitors. Additionally, pretreatment with inhibitors to FAK, PI3K and AKT led to a decrease in HBP-induced phosphorylation of p38/NF-κB axis. These results showed that HBP induced MCP-1 expression via a sequential activation of the FAK/PI3K/AKT pathway and p38 MAPK/NF-κB axis. Interestingly, the patterns of HBP regulation of the expression of the adhesion molecular VCAM-1 were similar to those seen in MCP-1 after pretreatment with inhibitors (or not). These findings may help to determine key pharmacological points of intervention, thus slowing the progress of inflammatory-mediated responses in certain diseases where inflammation is detrimental to the host.

炎症的特征在于多形核中性粒细胞（PMN）的早期流入，然后是第二波单核细胞募集。PMN通过释放肝素结合蛋白（HBP）来介导单核细胞募集，HBP激活单核细胞上的CCR2（CC趋化因子受体2）。但是，这种信号传输的途径仍然未知。越来越多的证据突出了白细胞与内皮细胞相互作用在炎症发作中的重要性。在这项研究中，一个有趣的发现是HBP增强了来自第三方内皮细胞（EC）的CCR2配体单核细胞趋化蛋白1（MCP-1）的分泌。在蛋白质，mRNA和分泌水平上证实了HBP诱导的MCP-1产量增加。ECs接触HBP会引起FAK / PI3K / AKT和p38 MAPK /NF-κB信号快速磷酸化。通过用FAK抑制剂（或siRNA），PI3K抑制剂，AKT抑制剂，p38抑制剂（或siRNA）和两种NF-κB抑制剂预处理，在HBP刺激反应期间MCP-1水平降低。此外，用FAK，PI3K和AKT抑制剂预处理可导致HBP诱导的p38 /NF-κB轴磷酸化降低。这些结果表明，HBP通过依次激活FAK / PI3K / AKT途径和p38 MAPK /NF-κB轴来诱导MCP-1表达。有趣的是，HBP调节粘附分子VCAM-1表达的模式与用抑制剂预处理（或不使用）后的MCP-1相似。这些发现可能有助于确定干预的关键药理学点，