Differential effects of apoptotic versus lysed cells on macrophage production of cytokines: Role of proteases
Differential effects of apoptotic versus lysed cells on macrophage production of cytokines: Role of proteases
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DOI：
10.4049/jimmunol.166.11.6847
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发表时间：
2001-06-01
影响因子：
4.4
通讯作者：
Henson, PM
中科院分区：
文献类型：
--
作者：
Fadok, VA;Bratton, DL;Henson, PM
经历凋亡的粒细胞在其溶解之前被吞噬细胞识别并去除。蛋白酶和其他有毒的细胞内物质释放到组织中会造成严重的损伤，延长炎症反应。巨噬细胞对凋亡细胞的结合和/或摄取通过涉及抗炎介质（包括TGF-β）的机制抑制促炎细胞因子的释放。为了模拟坏死细胞对巨噬细胞细胞因子产生的直接影响，我们在不存在血清的情况下向小鼠和人巨噬细胞中加入裂解或凋亡的中性粒细胞和淋巴细胞以避免补体激活。结果证实了裂解的中性粒细胞而不是淋巴细胞显著刺激巨噬细胞炎性蛋白2或IL-8、TNF-α和IL-10产生的能力。同时，裂解的中性粒细胞对TGF-β 1的诱导作用显著低于凋亡细胞。添加选定的丝氨酸蛋白酶抑制剂和抗人弹性蛋白酶抗体显着降低促炎作用，裂解的中性粒细胞，然后表现为类似于完整的凋亡细胞的炎症刺激。将溶解的中性粒细胞分离成膜和可溶性组分表明中性粒细胞膜表现为凋亡细胞。因此，当巨噬细胞暴露于裂解的中性粒细胞时观察到的细胞因子应答主要是由于释放的蛋白酶。因此，我们认为抗炎信号可以由含PtdSer的细胞膜给出，无论是来自早期凋亡、晚期凋亡还是裂解的细胞，但可以被裂解过程中释放的蛋白酶克服。因此，炎症反应的结果和受损细胞内Ag的潜在免疫原性将由哪个信号占主导地位决定。
Granulocytes undergoing apoptosis are recognized and removed by phagocytes before their lysis. The release of their formidable arsenal of proteases and other toxic intracellular contents into tissues can create significant damage, prolonging the inflammatory response. Binding and/or uptake of apoptotic cells by macrophages inhibits release of proinflammatory cytokines by mechanisms that involve anti-inflammatory mediators, including TGF-beta. To model the direct effects of necrotic cells on macrophage cytokine production, we added lysed or apoptotic neutrophils and lymphocytes to mouse and human macrophages in the absence of serum to avoid complement activation. The results confirmed the ability of lysed neutrophils, but not lymphocytes, to significantly stimulate production of macrophage-inflammatory protein 2 or IL-8, TNF-alpha, and IL-10. Concomitantly, induction of TGF-beta1 by lysed neutrophils was significantly lower than that observed for apoptotic cells. The addition of selected serine protease inhibitors and anti-human elastase Ab markedly reduced the proinflammatory effects, the lysed neutrophils then behaving as an antiinflammatory stimulus similar to intact apoptotic cells. Separation of lysed neutrophils into membrane and soluble fractions showed that the neutrophil membranes behaved like apoptotic cells. Thus, the cytokine response seen when macrophages were exposed to lysed neutrophils was largely due to liberated proteases. Therefore, we suggest that anti-inflammatory signals can be given by PtdSer- containing cell membranes, whether from early apoptotic, late apoptotic, or lysed cells, but can be overcome by proteases liberated during Iysis. Therefore, the outcome of an inflammatory reaction and the potential immunogenicity of Ags within the damaged cell will be determined by which signals predominate.