Hoffman M, Pratt C W, Corbin L W, Church F C
Department of Pathology, University of North Carolina School of Medicine, Chapel Hill.
J Leukoc Biol. 1990 Aug;48(2):156-62. doi: 10.1002/jlb.48.2.156.
The physiological function of the serpin (serine proteinase inhibitor) heparin cofactor II (HCII) is not well understood. A role for HCII as an inhibitor of thrombin in the presence of dermatan sulfate and heparin has been proposed. Neutrophils (PMN) are the major cellular component of acute inflammation. HCII can be proteolytically inactivated by cathepsin G (CG) and elastase (LE), which are released by stimulated PMN. We have recently shown that reaction products of HCII with CG and LE are potent chemotaxins for PMN. Monocytes (monos) appear later in the course of inflammation than do PMN. They differentiate into macrophages in the tissues and participate in healing of damaged tissue and initiating immune responses. We found that the proteolysis products of HCII were chemotactic for monocytes in a fashion similar to their effects on PMN. At 10(-8) to 10(-9) M, the chemotactic activity of HCII proteolysis products was comparable to that of 10(-8) M N-formyl-Met-Leu-Phe (fMLP). The chemotactic activity of HCII-proteinase reaction products is mediated by a different mechanism than that of alpha 1 proteinase inhibitor (alpha 1 PI)-LE complexes or fMLP. Our data suggest that chemotactic activity generated by proteolysis of HCII is not due to the conformational change induced by cleavage of the exposed loop near the reactive site nor by release of the reactive site peptide. We also compared the effects of HCII reaction products and fMLP on expression of Mac-1 and p150,95 adhesive proteins. Mac-1 has been implicated in mono adhesion and chemotaxis and as a potential initiator of coagulation. The surface expression of Mac-1 was not increased above control levels by incubation of leukocytes with HCII digests, even though fMLP did increase surface Mac-1. Proteolysis products of HCII could play a role in the initial influx of PMN into a thrombus, and in the transition from acute to chronic inflammation, or to granulation and healing.
丝氨酸蛋白酶抑制剂（serpin）类的肝素辅因子II（HCII）的生理功能尚未完全明确。有人提出HCII在硫酸皮肤素和肝素存在的情况下可作为凝血酶的抑制剂发挥作用。中性粒细胞（PMN）是急性炎症的主要细胞成分。HCII可被受刺激的PMN释放的组织蛋白酶G（CG）和弹性蛋白酶（LE）通过蛋白水解作用使其失活。我们最近发现，HCII与CG和LE的反应产物是PMN的强效趋化因子。单核细胞（monos）在炎症过程中比PMN出现得晚。它们在组织中分化为巨噬细胞，参与受损组织的愈合并启动免疫反应。我们发现，HCII的蛋白水解产物对单核细胞具有趋化作用，其方式与对PMN的作用类似。在10^(-8)至10^(-9) M浓度下，HCII蛋白水解产物的趋化活性与10^(-8) M的N-甲酰甲硫氨酰亮氨酰苯丙氨酸（fMLP）相当。HCII-蛋白酶反应产物的趋化活性是由一种不同于α1蛋白酶抑制剂（α1 PI）-LE复合物或fMLP的机制介导的。我们的数据表明，HCII蛋白水解产生的趋化活性并非由于反应位点附近暴露环的切割所诱导的构象变化，也不是由于反应位点肽的释放。我们还比较了HCII反应产物和fMLP对Mac-和p150,95黏附蛋白表达的影响。Mac-1与单核细胞黏附和趋化有关，并且是凝血的潜在启动因子。尽管fMLP确实增加了表面Mac-1，但用HCII消化产物孵育白细胞后，Mac-1的表面表达并未增加到对照水平以上。HCII的蛋白水解产物可能在PMN最初流入血栓以及从急性炎症向慢性炎症的转变，或向肉芽形成和愈合过程中发挥作用。
