Strassmann G, Graber N, Goyert S M, Fong M, McCullers S, Rong G W, Beall L D
Department of Immunology, Otsuka America Pharmaceutical Inc., Rockville, MD 20850.
J Immunol. 1994 Sep 1;153(5):2239-47.
The binding and trans-endothelium migration of inflammatory cells is believed to play a critical role in a variety of inflammatory conditions. This study investigates the ability of the experimental drug suramin to block the activation of HUVEC by endotoxin and by the proinflammatory cytokines IL-1 and TNF. We demonstrate that the inducible expression of several adhesion molecules by LPS and IL-1 beta but not by TNF-alpha is prevented by suramin. In a dose-dependent manner, suramin inhibits the binding of neutrophils and T lymphocytes to LPS and IL-1 beta but not to TNF-alpha-activated HUVEC. The inhibitory effect of the drug on IL-1 beta-induced but not on LPS-induced cell stimulation can be completely reversed by the addition of excess cytokine but not by excess LPS. Because LPS activation of HUVEC is known to depend on serum/plasma-derived soluble CD14, we set out to determine whether suramin inhibition involves interference with the action of the CD14-LPS complex on HUVEC. Indeed, the drug prevents the binding of radioactive LPS in the presence of serum and inhibits LPS-induced cell activation in serum-free medium supplemented with recombinant soluble CD14. The results suggest that suramin interferes with the CD14-dependent activation of HUVEC and that it also may be a useful agent in blocking infectious endotheliopathies in vivo.
炎症细胞的黏附和跨内皮迁移被认为在多种炎症状态中起关键作用。本研究调查了实验药物苏拉明阻断内毒素以及促炎细胞因子白细胞介素 -1（IL-1）和肿瘤坏死因子（TNF）激活人脐静脉内皮细胞（HUVEC）的能力。我们证明，苏拉明可阻止脂多糖（LPS）和IL-1β而非TNF-α诱导的几种黏附分子的表达。苏拉明以剂量依赖的方式抑制中性粒细胞和T淋巴细胞与LPS和IL-1β激活的HUVEC结合，但不抑制与TNF-α激活的HUVEC结合。该药物对IL-1β诱导而非LPS诱导的细胞刺激的抑制作用可通过添加过量细胞因子完全逆转，但添加过量LPS则不能。由于已知HUVEC的LPS激活依赖于血清/血浆来源的可溶性CD14，我们着手确定苏拉明的抑制作用是否涉及干扰CD14-LPS复合物对HUVEC的作用。实际上，该药物在有血清存在的情况下可阻止放射性LPS的结合，并在补充重组可溶性CD14的无血清培养基中抑制LPS诱导的细胞激活。结果表明，苏拉明干扰HUVEC的CD14依赖性激活，并且它在体内阻断感染性内皮病变方面可能也是一种有用的药物。
