Nfkb1 inhibits LPS-induced IFN-β and IL-12 p40 production in macrophages by distinct mechanisms.
Nfkb1 inhibits LPS-induced IFN-β and IL-12 p40 production in macrophages by distinct mechanisms.
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DOI：
10.1371/journal.pone.0032811
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Horwitz BH
中科院分区：
文献类型：
--
作者：
Zhao X;Ross EJ;Wang Y;Horwitz BH
在LPS刺激后，Nfkb 1缺陷型小鼠巨噬细胞表达比对照巨噬细胞更高水平的IFN-β和IL-12 p40，但这种现象的分子基础尚未完全确定。Nfkb 1编码几种基因产物，包括NF-κB亚基p50及其前体p105。p50来源于105的N-末端，并且p50同源二聚体在过表达时可以表现出抑制活性。p105的C末端区域对于LPS诱导的ERK活化是必需的，并且已经表明ERK活性在LPS刺激后抑制IFN-β和IL-12 p40。然而，尚未直接比较p50和p105的C-末端结构域在调节LPS刺激后巨噬细胞中内源性IFN-β（Ifnb）和IL-12 p40（Il 12 b）基因表达中的贡献。我们使用重组逆转录病毒在Nfkb 1缺陷小鼠骨髓源性巨噬细胞中以接近内源性水平表达p105、p50和p105的C端结构域（p105ΔN）。我们发现p50和p105ΔN均抑制Ifnb的表达，并且p105ΔN对Ifnb的抑制依赖于ERK激活，因为缺乏支持ERK激活所必需的关键丝氨酸的p105ΔN突变体（p105Δ NS 930 A）未能抑制Ifnb。相反，只有p105ΔN而不是p50抑制IL 12 b的表达。令人惊讶的是，p105Δ NS 930 A保留了对Il 12 b的抑制活性，表明ERK活化不是抑制所必需的。p105Δ NS 930 A对Ifnb和Il 12 b表达的差异作用与其结合伴侣c-Rel的功能呈负相关。这提示p105Δ NS 930 A可能通过干扰c-Rel的功能而影响基因表达。这些结果表明，Nfkb 1表现出多种基因特异性抑制功能后TLR刺激的小鼠巨噬细胞。
Nfkb1-deficient murine macrophages express higher levels of IFN-β and IL-12 p40 following LPS stimulation than control macrophages, but the molecular basis for this phenomenon has not been completely defined. Nfkb1 encodes several gene products including the NF-κB subunit p50 and its precursor p105. p50 is derived from the N-terminal of 105, and p50 homodimers can exhibit suppressive activity when overexpressed. The C-terminal region of p105 is necessary for LPS-induced ERK activation and it has been suggested that ERK activity inhibits both IFN-β and IL-12 p40 following LPS stimulation. However, the contributions of p50 and the C-terminal domain of p105 in regulating endogenous IFN-β(Ifnb) and IL-12 p40 (Il12b) gene expression in macrophages following LPS stimulation have not been directly compared. We have used recombinant retroviruses to express p105, p50, and the C-terminal domain of p105 (p105ΔN) in Nfkb1-deficient murine bone marrow-derived macrophages at near endogenous levels. We found that both p50 and p105ΔN inhibited expression of Ifnb, and that inhibition of Ifnb by p105ΔN depended on ERK activation, because a mutant of p105ΔN (p105ΔNS930A) that lacks a key serine necessary to support ERK activation failed to inhibit. In contrast, only p105ΔN but not p50 inhibited Il12b expression. Surprisingly, p105ΔNS930A retained inhibitory activity for Il12b, indicating that ERK activation was not necessary for inhibition. The differential effects of p105ΔNS930A on Ifnb and Il12b expression inversely correlated with the function of one of its binding partners, c-Rel. This raised the possibility that p105ΔNS930A influences gene expression by interfering with the function of c-Rel. These results demonstrate that Nfkb1 exhibits multiple gene-specific inhibitory functions following TLR stimulation of murine macrophages.
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影响因子：
7.3
作者：
Cheng CS;Feldman KE;Lee J;Verma S;Huang DB;Huynh K;Chang M;Ponomarenko JV;Sun SC;Benedict CA;Ghosh G;Hoffmann A
通讯作者：
Hoffmann A
影响因子：
3.5
作者：
Masumi, A;Tamaoki, S;Komuro, K
通讯作者：
Komuro, K
影响因子：
4.4
作者：
Erdman, SE;Fox, JG;Horwitz, BH
通讯作者：
Horwitz, BH
DOI：
10.1073/pnas.89.6.2489
发表时间：
1992-03-15
影响因子：
11.1
作者：
HATADA, EN;NIETERS, A;SCHEIDEREIT, C
通讯作者：
SCHEIDEREIT, C
影响因子：
4.8
作者：
Salmerón, A;Janzen, J;Ley, SC
通讯作者：
Ley, SC