CULTURED HUMAN LIVER FAT-STORING CELLS PRODUCE MONOCYTE CHEMOTACTIC PROTEIN-1 - REGULATION BY PROINFLAMMATORY CYTOKINES
CULTURED HUMAN LIVER FAT-STORING CELLS PRODUCE MONOCYTE CHEMOTACTIC PROTEIN-1 - REGULATION BY PROINFLAMMATORY CYTOKINES
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DOI：
10.1172/jci116753
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发表时间：
1993-10-01
影响因子：
15.9
通讯作者：
ABBOUD, HE
中科院分区：
文献类型：
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作者：
MARRA, F;VALENTE, AJ;ABBOUD, HE
单核细胞在慢性肝脏炎症期间浸润门脉空间。单核细胞趋化蛋白-I（MCP-1）是诱导单核细胞趋化和活化的细胞因子。我们研究了人类肝脏脂肪储存细胞（FSC）是否分泌MCP-1，以及调节MCP-1产生的机制。未受刺激的FSC分泌MCP-1，如通过放射免疫测定以及趋化测定所测量的，并表达编码该细胞因子的mRNA。当用白细胞介素-1 α（IL-1 α）或干扰素-γ（IFN-γ）处理FSC时，观察到MCP-1分泌增加2 - 3倍。肿瘤坏死因子-α（TNF α）也增加MCP-1分泌，尽管程度较低（1.6倍）。北方印迹分析表明，IL-1 α和IFN-γ强烈地增加编码MCP-1的mRNA的水平，而TNF α似乎是较弱的刺激。通过十二烷基硫酸钠-聚丙烯酰胺凝胶电泳和免疫印迹分析FSC条件培养基，发现MCP-1的三个条带最有可能代表不同表观分子量的亚型。用蛋白激酶C抑制剂H-7预处理FSC，阻断了马槟榔诱导的MCP-1基因表达和分泌的增加。为了确定MCP-1在体内的潜在作用，我们还分析了正常和病理性人肝组织。北方印迹分析显示，MCP-1 mRNA在慢性活动性肝炎患者肝组织中的表达较正常肝组织丰富。这些研究表明FSC分泌的MCP-1受促炎细胞因子刺激，并且MCP-1基因表达在慢性炎症性肝病中上调。FSC释放的MCP-1可能参与肝损伤部位单核细胞的募集和激活。
Monocytes infiltrate the portal space during chronic liver inflammation. Monocyte chemotactic protein-I (MCP-1) is a cytokine that induces monocyte chemotaxis and activation. We investigated if human liver fat-storing cells (FSC) secrete MCP-1, and the mechanisms that regulate MCP-1 production. Unstimulated FSC secrete MCP-1 as measured by radioimmunoassay as well as a chemotactic assay and express mRNA that encodes for this cytokine. A two- to threefold increase in MCP-1 secretion was observed when FSC were treated with either interleukin-1alpha (IL-1alpha) or interferon-gamma (IFN-gamma). Tumor necrosis factor-alpha (TNFalpha) also increased MCP-1 secretion, although to a lesser extent (1.6-fold). Northern blot analysis showed that IL-1alpha and IFN-gamma strongly increase the levels of mRNA that encodes for MCP-1, whereas TNFalpha appears to be a weaker stimulus. Analysis of FSC-conditioned medium by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblotting revealed three bands of MCP-1 that most likely represent isoforms of different apparent molecular weights. Pretreatment of FSC with H-7, a protein kinase C inhibitor, blocked cytokine-induced increase in both MCP-1 gene expression and secretion. To determine the potential role of MCP-1 in vivo, we also analyzed normal and pathologic human liver tissue. Northern blot analysis showed that MCP-1 mRNA expression is more abundant in liver tissue obtained from patients with chronic active hepatitis compared with normal liver tissue. These studies indicate that MCP-1 secreted by FSC is stimulated by proinflammatory cytokines and that MCP-1 gene expression is upregulated in chronic inflammatory liver disease. MCP-1 released by FSC may participate in the recruitment and activation of monocytes at sites of liver injury.