Keap1 silencing boosts lipopolysaccharide-induced transcription of interleukin 6 via activation of nuclear factor ¦ÊB in macrophages
详细信息 查看全文
- 作者：Peng Lv ; Peng Xue ; Jian Dong ; Hui Peng ; Rebecca Clewell ; Aiping Wang ; Yue Wang ; Shuangqing Peng ; Weidong Qu ; Qiang Zhang ; Melvin E. Andersen ; Jingbo Pi
- 关键词：IL6 ; Nrf2 ; Keap1 ; IKK¦Â ; NF-¦ÊB ; Macrophage
- 刊名：Toxicology and Applied Pharmacology
- 出版年：2013
- 出版时间：1 November, 2013
- 年：2013
- 卷：272
- 期：3
- 页码：697-702
- 全文大小：889 K
文摘
Interleukin-6 (IL6) is a multifunctional cytokine that regulates immune and inflammatory responses. Multiple transcription factors, including nuclear factor ¦ÊB (NF-¦ÊB) and nuclear factor E2-related factor 2 (Nrf2), regulate IL6 transcription. Kelch-like ECH-associated protein 1 (Keap1) is a substrate adaptor protein for the Cullin 3-dependent E3 ubiquitin ligase complex, which regulates the degradation of many proteins, including Nrf2 and I¦ÊB kinase ¦Â (IKK¦Â). Here, we found that stable knockdown of Keap1 (Keap1-KD) in RAW 264.7 (RAW) mouse macrophages and human monocyte THP-1 cells significantly increased expression of Il6, and Nrf2-target genes, under basal and lipopolysaccharide (LPS, 0.001-0.1 ¦Ìg/ml)-challenged conditions. However, Nrf2 activation alone, by tert-butylhydroquinone treatment of RAW cells, did not increase expression of Il6. Compared to cells transduced with scrambled non-target negative control shRNA, Keap1-KD RAW cells showed enhanced protein levels of IKK¦Â and increased expression and phosphorylation of NF-¦ÊB p65 under non-stressed and LPS-treated conditions. Because the expression of Il6 in Keap1-KD RAW cells was significantly attenuated by silencing of Ikk¦Â, but not Nrf2, it appears that stabilized IKK¦Â is responsible for the enhanced transactivation of Il6 in Keap1-KD cells. This study demonstrated that silencing of Keap1 in macrophages boosts LPS-induced transcription of Il6 via NF-¦ÊB activation. Given the importance of IL6 in the inflammatory response, the Keap1-IKK¦Â-NF-¦ÊB pathway may be a novel target for treatment and prevention of inflammation and associated disorders.