Advanced oxidation protein products induce G1 phase arrest in intestinal epithelial cells via a RAGE/CD36-JNK-p27kip1 mediated pathway（肠上皮细胞G1期阻滞研究）

Jie Shi  ¹ , Shibo Sun  ² , Yan Liao  ¹ , Jing Tang  ³ , Xiaoping Xu  ⁴ , Biyan Qin  ¹ , Caolitao Qin  ¹ , Lishan Peng  ⁵ , Mengshi Luo  ⁵ , Lan Bai  ⁶ , Fang Xie  ⁷

• ¹ Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China.
• ² Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China.
• ³ Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, China.
• ⁴ Department of Gastroenterology, Hunan Provincial People’s Hospital, Changsha, Hunan, 410005, China.
• ⁵ Southern Medical University, Guangzhou, Guangdong, 510515, China.
• ⁶ Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China. Electronic address: bailan99@hotmail.com.
• ⁷ Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China. Electronic address: stellaff@126.com.

Abstract

Intestinal epithelial cell (IEC) cycle arrest has recently been found to be involved in the pathogenesis of Crohn’s disease (CD). However, the mechanism underlying the regulation of this form of cell cycle arrest, remains unclear. Here, we investigated the roles that advanced oxidation protein products (AOPPs) may play in regulating IEC cycle arrest. Plasma AOPPs levels and IEC cycle distributions were evaluated in 12 patients with CD. Molecular changes in various cyclins, cyclin-dependent kinases (CDKs), and other regulatory molecules were examined in cultured immortalized rat intestinal epithelial (IEC-6) cells after treatment with AOPPs. The in vivo effects exerted by AOPPs were evaluated using a normal C57BL/6 mouse model with an acute AOPPs challenge. Interestingly, plasma AOPPs levels were elevated in active CD patients and correlated with IEC G1 phase arrest. In addition, IEC treatment with AOPPs markedly reduced the expression of cyclin E and CDK2, thus sensitizing epithelial cells to cell cycle arrest both in vitro and in vivo. Importantly, we found that AOPPs induced IEC G1 phase arrest by modulating two membrane receptors, RAGE and CD36. Furthermore, phosphorylation of c-jun N-terminal kinase (JNK) and the expression of p27kip1 in AOPPs-treated cells were subsequently increased and thus affected cell cycle progression. Our findings reveal that AOPPs influence IEC cycle progression by reducing cyclin E and CDK2 expression through RAGE/CD36-depedent JNK/p27kip1 signaling. Consequently, AOPPs may represent a potential therapeutic molecule. Targeting AOPPs may offer a novel approach to managing CD.

Keywords: Advanced oxidation protein products; Cyclin E; Cyclin-dependent kinase 2; G1 phase arrest; p27kip1.