GENDER DIFFERENCE IN GRANULOCYTE DYNAMICS AND APOPTOSIS AND THE ROLE OF IL-18 DURING ENDOTOXIN-INDUCED SYSTEMIC INFLAMMATION
GENDER DIFFERENCE IN GRANULOCYTE DYNAMICS AND APOPTOSIS AND THE ROLE OF IL-18 DURING ENDOTOXIN-INDUCED SYSTEMIC INFLAMMATION
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DOI：
10.1097/shk.0b013e31819c358a
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发表时间：
2009-10-01
期刊：
影响因子：
3.1
通讯作者：
Usami, Makoto
中科院分区：
文献类型：
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作者：
Aoyama, Michiko;Kotani, Joji;Usami, Makoto
延迟的粒细胞凋亡与持续性炎症有关。虽然已知男性比女性更容易发生脓毒症，但其机制尚未完全了解。血清IL-18水平对应于全身炎症的严重程度。本研究的目的是阐明性别差异和IL-18对粒细胞动力学和细胞凋亡的影响。雄性和雌性野生型（WT）和IL-18敲除（KO）小鼠腹腔内注射LIDS。然后在注射后24 h内的不同时间收集骨髓细胞、外周血和腹膜细胞。通过膜联蛋白V染色，使用分化的粒细胞特异性Gr-1、B淋巴细胞特异性B220和巨噬细胞特异性F4/80抗体，使用三色流式细胞术评估细胞凋亡。雄性WT小鼠比雌性WT小鼠对内毒素更敏感（存活率，雄性WT为41%，雌性WT为84%）。雄性WT小鼠在髓样分化、髓样细胞从骨髓释放到外周以及迁移到炎症性腹膜腔中方面表现出比雌性小鼠更强的反应。雄性小鼠还表现出对腹膜腔中粒细胞凋亡的更大抑制，这也可能导致这些细胞的数量更高。WT和KO小鼠之间的比较显示，这些骨髓细胞/粒细胞行为的性别差异与内源性IL-18无关。然而，在腹腔内LPS后，WT小鼠血液中的IL-18水平在雄性中显著高于雌性，并且KO小鼠的存活率仅在雄性中显著高于WT小鼠。这表明内源性IL-18的产生仅降低雄性动物的存活率。因此，在全身性炎症状态期间，应将男性中不依赖于IL-18和其他IL-18依赖性危及生命因素的过度骨髓/粒细胞免疫作为治疗靶点。
Delayed granulocyte apoptosis is implicated in persistent inflammation. Although it is known that males develop sepsis more easily than females, the mechanism for this is not fully understood. Serum IL-18 levels correspond to severity of systemic inflammation. The purpose of this study was to elucidate gender differences and the effects of IL-18 on granulocyte dynamics and apoptosis. Male and female wild-type (WT) and IL-18 knockout (KO) mice were injected intraperitoneally with LIDS. Bone marrow cells, peripheral blood, and peritoneal cells were then collected at different times up to 24 h after injection. Apoptosis was assessed by annexin V staining using three-color flow cytometry with differentiated granulocyte-specific Gr-1, B-lymphocyte-specific B220, and macrophage-specific F4/80 antibodies. Male WT mice were more susceptible to endotoxin than female WT mice (survival rate, 41% in male WT and 84% in female WT). Male WT mice showed stronger responses than females in myeloid differentiation, release of myeloid cells from the bone marrow into the periphery, and migration into the inflammatory peritoneal cavity. Male mice also showed greater inhibition of granulocyte apoptosis in the peritoneal cavity, which might also contribute to the higher numbers of those cells present. A comparison between WT and KO mice revealed that the gender difference in these myeloid cells/granulocytes' behaviors was independent of endogenous IL-18. Nevertheless, levels of IL-18 in the blood of WT mice were significantly higher in males than in females after intraperitoneal LPS, and the survival rate was significantly higher in KO mice compared with WT mice only in males. This indicates that endogenous IL-18 production decreases survival only in males. Thus, excessive myeloid/granulocyte immunity independent of IL-18 and other IL-18-dependent life-threatening factors in males should be taken into account as therapeutic targets during systemic inflammatory states.