Cigarette smoke-induced oxidative stress suppresses generation of dendritic cell IL-12 and IL-23 through ERK-dependent pathways.
Cigarette smoke-induced oxidative stress suppresses generation of dendritic cell IL-12 and IL-23 through ERK-dependent pathways.
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DOI：
10.4049/jimmunol.181.2.1536
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发表时间：
2008-07-15
期刊：
影响因子：
--
通讯作者：
Vassallo R
中科院分区：
文献类型：
--
作者：
Kroening PR;Barnes TW;Pease L;Limper A;Kita H;Vassallo R
白介素-12p70 [IL-12p70]是由p35和p40亚基组成的异源二聚体，是成熟树突状细胞（dc）产生的关键极化细胞因子。我们报道了香烟烟雾提取物(CSE) -一种可溶性香烟烟雾成分的提取物-抑制脂多糖（Lps）或cd40l成熟dc产生p35和p40。成熟dc中IL-12p70产生的抑制未在CSE中达到的尼古丁浓度存在或吸烟者循环中观察到。通过用抗氧化剂n -乙酰半胱氨酸（NAC）和过氧化氢酶预处理DCs或CSE，恢复CSE条件下抑制的IL-12p70蛋白的产生。CSE抑制DC IL-12p70需要激活ERK依赖通路，因为ERK的抑制消除了CSE对IL-12分泌的抑制作用。氧化应激和CSE对ERK的持续磷酸化提高了未成熟和成熟dc中p40转录抑制因子c-fos的核水平。CSE对p40亚基的抑制也导致成熟dc中IL-23蛋白的产生减少。使用慢性香烟烟雾暴露的小鼠模型，我们观察到来自“吸烟者”小鼠的全身和肺部dc在成熟后产生的IL-12p70和p40蛋白显著减少。这种抑制作用是选择性的，因为在“吸烟者”中，DC成熟过程中tnf - α的产生增强。这些数据表明，暴露于香烟烟雾中产生的氧化应激通过激活erk依赖性通路使DCs成熟，从而抑制关键细胞因子的产生。一些香烟引起的对DC功能的抑制作用可以通过抗氧化剂来减轻。
Interleukin-12p70 [IL-12p70], a heterodimer composed of p35 and p40 subunits, is a key polarizing cytokine produced by maturing dendritic cells (DCs). We report that cigarette smoke extract (CSE) – an extract of soluble cigarette smoke components – suppresses both p35 and p40 production by lipopolysaccharide (Lps) or CD40L-matured DCs. Suppression of IL-12p70 production from maturing DCs was not observed in the presence of nicotine concentrations achievable in CSE, or in the circulation of smokers. The suppressed IL-12p70 protein production by CSE-conditioned DCs was restored by pre-treatment of DCs or CSE with the anti-oxidants N-acetyl cysteine (NAC) and catalase. Inhibition of DC IL-12p70 by CSE required activation of ERK-dependent pathways, since inhibition of ERK abrogated the suppressive effect of CSE on IL-12 secretion. Oxidative stress and sustained ERK phosphorylation by CSE enhanced nuclear levels of the p40 transcriptional repressor c-fos in both immature and maturing DCs. Suppression of the p40 subunit by CSE also resulted in diminished production of IL-23 protein by maturing DCs. Using a murine model of chronic cigarette smoke exposure, we observed that systemic and lung DCs from mice “smokers” produced significantly less IL-12p70 and p40 protein upon maturation. This inhibitory effect was selective, since production of TNF-alpha during DC maturation was enhanced in the “smokers”. These data imply that oxidative stress generated by cigarette smoke exposure suppresses the generation of key cytokines by maturing DCs through the activation of ERK-dependent pathways. Some of the cigarette smoke-induced inhibitory effects on DC function may be mitigated by anti-oxidants.
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DOI：
10.1152/ajplung.2001.280.6.l1189
发表时间：
2001-06-01
影响因子：
4.9
作者：
Ishii, T;Matsuse, T;Ouchi, Y
通讯作者：
Ouchi, Y
影响因子：
5.8
作者：
Kode, Aruna;Yang, Se-Ran;Rahman, Irfan
通讯作者：
Rahman, Irfan
DOI：
10.1084/jem.20051047
发表时间：
2005-12-19
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Hegazi RA;Rao KN;Mayle A;Sepulveda AR;Otterbein LE;Plevy SE
通讯作者：
Plevy SE
影响因子：
4.8
作者：
Aggarwal, S;Ghilardi, N;Gurney, AL
通讯作者：
Gurney, AL
影响因子：
4.4
作者：
Agrawal, Anshu;Dillon, Stephanie;Pulendran, Bali
通讯作者：
Pulendran, Bali