A role for NF-κB subunits p50 and p65 in the inhibition of lipopolysaccharide-induced shock
A role for NF-κB subunits p50 and p65 in the inhibition of lipopolysaccharide-induced shock
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DOI：
10.4049/jimmunol.173.9.5786
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发表时间：
2004-11-01
影响因子：
4.4
通讯作者：
Horwitz, BH
中科院分区：
文献类型：
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作者：
Gadjeva, M;Tomczak, MF;Horwitz, BH
为了评估NF-κ B亚基p50和p65在限制内毒素诱导的全身炎症反应中的作用的可能性，我们比较了野生型（WT）、p65（+/-）、p50（-/-）和p50（-/-）p65（+/-）（3X）小鼠对LPS诱导的休克的易感性。有趣的是，p65（+/-）小鼠对LPS诱导的休克并不比WT小鼠更敏感，而3X小鼠对LPS的毒性作用非常敏感。单独缺乏p50的小鼠显示中间表型。对LPS的敏感性是先天免疫系统的特性，其特征在于p50（-/-）和3X小鼠中循环TNF水平升高。LPS诱导休克的能力依赖于TNF，3X小鼠比p50缺陷小鼠对TNF的毒性作用明显更敏感。p50（-/-）小鼠脾脏中几种LPS诱导的促炎基因（包括IFN-γ）的表达显著高于WT小鼠脾脏中的表达，有趣的是，IFN-γ的表达在3X小鼠脾脏中进一步增强。这些结果表明，NF-κ B亚基p50和p65在对LPS的全身反应过程中具有关键的抑制功能，并提高了这些功能在预防与全身炎症反应综合征相关的死亡率中是必不可少的可能性。
To evaluate the possibility that NF-kappaB subunits p50 and p65 have a role in limiting the systemic inflammatory response induced by endotoxin, we compared the susceptibility of wild-type (WT), p65(+/-), p50(-/-), and p50(-/-)p65(+/-) (3X) mice to LPS-induced shock. Interestingly, whereas p65(+/-) mice were no more sensitive than WT mice to LPS-induced shock, 3X mice were exquisitely sensitive to the toxic effects of LPS. Mice lacking p50 alone displayed an intermediate phenotype. Sensitivity to LPS was a property of the innate immune system and was characterized by elevated circulating levels of TNF in both p50(-/-) and 3X mice. The ability of LPS to induce shock depended upon TNF, and 3X mice were significantly more sensitive to the toxic effects of TNF than were p50-deficient mice. The expression of several LPS-inducible proinflammatory genes, including IFN-gamma, was significantly higher within the spleens of p50(-/-) mice than in the spleens of WT mice, and interestingly, the expression of IFN-gamma was augmented still further within the spleens of 3X mice. These results demonstrate that NF-kappaB subunits p50 and p65 have critical inhibitory functions during the systemic response to LPS and raise the possibility that these functions could be essential in preventing mortality associated with systemic inflammatory response syndromes.