Caspase 1-independent activation of interleukin-1beta in neutrophil-predominant inflammation.
Caspase 1-independent activation of interleukin-1beta in neutrophil-predominant inflammation.
复制标题
DOI：
10.1002/art.24959
复制
发表时间：
2009-12
影响因子：
--
通讯作者：
Corr, Maripat
中科院分区：
文献类型：
--
作者：
Guma, Monica;Ronacher, Lisa;Liu-Bryan, Ru;Takai, Shinji;Karin, Michael;Corr, Maripat
IL-1β是与急性关节炎发病机制相关的关键细胞因子。胱天蛋白酶-1、中性粒细胞弹性蛋白酶和糜蛋白酶都将pro-IL-1β加工成其生物活性形式。这些蛋白酶的潜在贡献进行了检查。在用弹性蛋白酶或糜蛋白酶抑制剂进行免疫治疗的同时，检测了Caspase-1（Casp 1 −/−）缺陷型和野生型（WT）小鼠对K/BxN致关节炎血清转移和尿酸盐（MSU）晶体诱导的腹膜炎的反应。通过ELISA和Western印迹测试关节炎爪中IL-1β蛋白的存在。在存在蛋白酶抑制剂的情况下，检测WT和突变小鼠的中性粒细胞和肥大细胞在体外刺激后分泌IL-1β的能力。在K/BxN血清转移关节炎模型中，Casp 1 −/−和WT小鼠出现相同程度的爪肿胀。将MSU晶体注射到Casp 1 −/−小鼠中也导致中性粒细胞流入和可测量的腹膜IL-1β蛋白。中性粒细胞弹性蛋白酶抑制剂可减弱这两种反应。K/BxN血清诱导的关节炎也减少了治疗与糜蛋白酶抑制剂。在LPS体外刺激时，Casp 1 −/−中性粒细胞和肥大细胞分泌相似量的IL-1β蛋白，尽管当Casp 1 −/−中性粒细胞暴露于MSU晶体时，其水平低于WT细胞。弹性蛋白酶和糜蛋白酶抑制剂减少这些细胞释放的IL-1β。中性粒细胞和肥大细胞产生IL-1β并不完全依赖于caspase-1，其他蛋白酶可以补偿体内caspase-1的损失。因此，这些途径可能会影响caspase-1靶向治疗嗜中性粒细胞为主的关节炎。
IL-1β is a key cytokine linked to the pathogenesis of acute arthritis. Caspase-1, neutrophil elastase, and chymase all process pro-IL-1β to its biologically active form. The potential contributions of these proteases were examined. Caspase-1 (Casp1−/−) deficient and wild type (WT) mice were tested for their response to K/BxN arthritogenic serum transfer and monosodium urate (MSU) crystal induced peritonitis while prophylactically treated with elastase or chymase inhibitors. Arthritic paws were tested for presence of IL-1β protein by ELISA and Western blot. Neutrophils and mast cells from WT and mutant mice were tested for their ability to secrete IL-1β after in vitro stimulation in the presence of protease inhibitors. Casp1−/− and WT mice developed paw swelling to the same extent in the K/BxN serum transfer arthritis model. MSU crystal injection into Casp1−/− mice also resulted in neutrophil influx and measurable peritoneal IL-1β protein. Both of these responses were attenuated with neutrophil elastase inhibitors. K/BxN serum induced arthritis was also reduced by treatment with a chymase inhibitor. Casp1−/− neutrophils and mast cells secreted similar amounts of IL-1β protein upon in vitro stimulation with LPS, albeit at lower levels than WT cells when Casp1−/− neutrophils were exposed to MSU crystals. Elastase and chymase inhibitors reduced IL-1β released by these cells. The production of IL-1β by neutrophils and mast cells is not exclusively dependent on caspase-1 and other proteases can compensate for loss of caspase-1 in vivo. These pathways might therefore compromise the caspase-1 targeted therapies in neutrophil-predominant arthritis.
登录
查看更多内容
影响因子：
4.4
作者：
Corr, M;Crain, B
通讯作者：
Crain, B
影响因子：
16
作者：
Martinon, F;Burns, K;Tschopp, J
通讯作者：
Tschopp, J
影响因子：
15.9
作者：
Kessenbrock, Kai;Froehlich, Leopold;Jenne, Dieter E.
通讯作者：
Jenne, Dieter E.
影响因子：
4.4
作者：
Campbell, EJ;Campbell, MA;Owen, CA
通讯作者：
Owen, CA
影响因子：
56.9
作者：
Lee, DM;Friend, DS;Brenner, MB
通讯作者：
Brenner, MB