Secretory leukocyte protease inhibitor suppresses the production of monocyte prostaglandin H synthase-2, prostaglandin E(2), and matrix metalloproteinases
Secretory leukocyte protease inhibitor suppresses the production of monocyte prostaglandin H synthase-2, prostaglandin E(2), and matrix metalloproteinases
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DOI：
10.1172/jci119254
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发表时间：
1997-03-01
影响因子：
15.9
通讯作者：
Wahl, LM
中科院分区：
文献类型：
--
作者：
Zhang, YH;DeWitt, DL;Wahl, LM
分泌性白细胞蛋白酶抑制剂（SLPI）是一种丝氨酸蛋白酶抑制剂，存在于粘膜表面的液体中。除了作为抗蛋白酶的主要功能外，SLPI还可能影响与酶合成和逆转录病毒感染相关的细胞功能。本研究检测了SLPI对单核细胞产生基质金属蛋白酶（MMPs）的影响。在用刀豆球蛋白A（concanavalin A）或脂多糖（LPS）刺激前加入SLPI可显著抑制单核细胞前列腺素H合酶-2（PGHS-2），PGHS-2是PGE（2）-cAMP依赖的单核细胞MMPs合成途径中的关键酶。用0.1 μ g/ml的SLPI检测到PGHS-2的抑制，在1和10 μ g/ml时有实质性抑制。SLPI对PGHS-2的抑制作用伴随着PGE（2）产生的减少，导致间质胶原酶（MMP-1）和明胶酶B（MMP-9）的抑制，而PGE（2）或Bt（2）cAMP可逆转这种抑制作用。SLPI的抑制作用在很大程度上独立于其抗蛋白酶活性，因为SLPI突变蛋白，具有显着较低的抗蛋白酶活性，也抑制PGHS-2和MMP的诱导。SLPI的抑制作用不涉及单核因子产生的调节，因为TNF-α和IL-10不受影响。这些发现表明，SLPI还通过干扰导致单核细胞MMP产生的信号转导途径作为有效的抗肿瘤剂发挥作用。
Secretory leukocyte protease inhibitor (SLPI) is a serine protease inhibitor found in fluids lining mucosal surfaces. In addition to its primary function as an antiprotease, SLPI may also influence cellular functions associated with enzyme synthesis and retroviral infection. In this study, SLPI was examined for its effect on signaling events involved in the production of matrix metalloproteinases (MMPs) by monocytes, Addition of SLPI before stimulation with concanavalin A or LPS resulted in a significant inhibition of monocyte prostaglandin H synthase-2 (PGHS-2), a pivotal enzyme in the PGE(2)-cAMP dependent pathway of monocyte MMP synthesis. Suppression of PGHS-2 was detected with 0.1 mu g/ml of SLPI with a substantial inhibition at 1 and 10 mu g/ml. Attenuation of PGHS-2 by SLPI was accompanied by decreased production of PGE(2) resulting in the suppression of interstitial collagenase (MMP-1) and gelatinase B (MMP-9) that was reversed by PGE(2) or Bt(2)cAMP. The inhibitory effect of SLPI was largely independent of its antiprotease activity because SLPI muteins, with significantly lower antiprotease activity, also suppressed the induction of PGHS-2 and MMPs. The inhibitory effects of SLPI did not involve the modulation of monokine production since TNF-alpha and IL-10 were unaffected. These findings demonstrate that SLPI also functions as a potent antiinflammatory agent by interfering with the signal transduction pathway leading to monocyte MMP production.