Aziz Khalil A, Till Kathleen J, Chen Haijuan, Slupsky Joseph R, Campbell Fiona, Cawley John C, Zuzel Mirko
Department of Haematology, University of Liverpool, Liverpool, United Kingdom.
Blood. 2003 Aug 1;102(3):1051-6. doi: 10.1182/blood-2002-12-3737. Epub 2003 Apr 10.
Bone marrow (BM) fibrosis is a central diagnostic and pathogenetic feature of hairy-cell leukemia (HCL). It is known that fibronectin (FN) produced and assembled by the malignant hairy cells (HCs) themselves is a major component of this fibrosis. It is also known that FN production is greatly enhanced by adhesion of HCs to hyaluronan (HA) via CD44. The aim of the present study was to establish the roles of fibrogenic autocrine cytokines (fibroblast growth factor-2 [FGF-2] and transforming growth factor beta [TGFbeta]) and of different isoforms of CD44 in this FN production. We show that HC adhesion to HA stimulates FGF-2, but not TGFbeta, production and that HCs possess FGF-2 receptor. In a range of experiments, FN production was greatly reduced by blocking FGF-2 but not TGFbeta. Moreover FN, but not FGF-2, secretion was blocked by down-regulation of the v3 isoform of CD44 and by addition of heparitinase. These results show that autocrine FGF-2 secreted by HCs is the principal cytokine responsible for FN production by these cells when cultured on HA. The central role of FGF-2 in the pathogenesis of the BM fibrosis of HCL was supported by our immunohistochemical demonstration of large amounts of this cytokine in fibrotic BM but not in HCL spleen where there is no fibrosis. As regards CD44 isoforms, the present work demonstrates that CD44v3 is essential for providing the heparan sulfate necessary for HC stimulation by FGF-2, whereas the signal for production of the cytokine was provided by HA binding to CD44H, the standard hematopoietic form of the molecule.
骨髓（BM）纤维化是毛细胞白血病（HCL）的核心诊断和发病机制特征。已知由恶性毛细胞（HCs）自身产生和组装的纤连蛋白（FN）是这种纤维化的主要成分。还已知HCs通过CD44与透明质酸（HA）黏附可大大增强FN的产生。本研究的目的是确定促纤维化自分泌细胞因子（成纤维细胞生长因子-2 [FGF-2]和转化生长因子β [TGFβ]）以及不同亚型的CD44在这种FN产生中的作用。我们发现HCs与HA的黏附刺激FGF-2而非TGFβ的产生，并且HCs拥有FGF-2受体。在一系列实验中，通过阻断FGF-2可使FN产生大幅减少，而阻断TGFβ则无此效果。此外，下调CD44的v3亚型以及添加肝素酶可阻断FN而非FGF-2的分泌。这些结果表明，当在HA上培养时，HCs分泌的自分泌FGF-2是这些细胞产生FN的主要细胞因子。我们通过免疫组织化学证明在纤维化的BM中有大量这种细胞因子，而在无纤维化的HCL脾脏中则没有，这支持了FGF-2在HCL的BM纤维化发病机制中的核心作用。关于CD44亚型，目前的研究表明CD44v3对于提供FGF-2刺激HCs所需的硫酸乙酰肝素至关重要，而细胞因子产生的信号则由HA与该分子的标准造血形式CD44H结合提供。
