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Apurinic/Apyrimidinic Endonuclease 1 Is a Key Modulator of Keratinocyte Inflammatory Responses¹

Hye-Mi Lee,^*¶ Jae-Min Yuk,^*¶ Dong-Min Shin,^*¶ Chul-Su Yang,^*¶ Kwang-Kyu Kim,^*¶ Dae-Kyoung Choi, Zhe-Long Liang, Jin-Man Kim,^¶|| Byeong Hwa Jeon,^¶|| Chang Deok Kim,^|| Jeung-Hoon Lee,^|| and Eun-Kyeong Jo^2*¶||

^*Department of Microbiology, Department of Dermatology, Department of Pathology, Department of Physiology, ^¶Infection Signaling Network Research Center, and ^||Research Institute for Medical Sciences, College of Medicine, Chungnam National University, Daejeon, South Korea

Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1) functions in both DNA repair and redox signaling, making it an attractive emerging therapeutic target. However, the role of APE1 in cutaneous inflammatory responses is largely unknown. In this study, we report that APE1 is a key upstream regulator in TLR2-dependent keratinocyte inflammatory responses. We found that nuclear expression of APE1 in epidermal layers was markedly up-regulated in psoriatic skin. APE1 was essential for the transcriptional activation and nuclear translocation of hypoxia-inducible factor-1 and NF-B, both of which are crucial for inflammatory signaling in keratinocytes. Moreover, APE1 played a crucial role in the expression of TLR2-mediated inflammatory mediators, including TNF-, CXCL8, and LL-37, in HaCaT cells and human primary keratinocytes. Silencing of APE1 attenuated cyclin D1/cyclin-dependent kinase 4 expression and phosphorylation of ERK1/2 and Akt, thereby affecting keratinocyte proliferation. Importantly, TLR2-induced generation of reactive oxygen species contributed to the nuclear translocation and expression of APE1, suggesting an autoregulatory circuit in which the subcellular localization of APE1 is associated with the production of APE1 per se through reactive oxygen species-dependent signaling. Taken together, these findings establish a role for APE1 as a master regulator of TLR2-dependent inflammatory responses in human keratinocytes.

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¹ This work was supported by the Korea Science and Engineering Foundation through the Infection Signaling Network Research Center (Grant R13-2007-020-01000-0) at Chungnam National University.

² Address correspondence and reprint requests to Dr. Eun-Kyeong Jo, Infection Signaling Network Research Center, College of Medicine, Chungnam National University, 6 Munhwa-dong, Jungku, Daejeon 301-747, South Korea. E-mail address: hayoungj{at}cnu.ac.kr

³ Abbreviations used in this paper: APE1, apurinic/apyrimidinic endonuclease 1/redox factor-1; Cdk, cyclin-dependent kinase; DAPI, 4',6-diamidino-2-phenylindole; DPI, diphenylene iodonium; HIF, hypoxia-inducible factor; HMGB, high-mobility group box; NAC, N-acetylcysteine; poly(I:C), polyinosinic:polycytidylic acid; RNAi, RNA interference; ROS, reactive oxygen species; shAPE1, APE1-specific siRNA; shRNA, small hairpin RNA; shNS, nonspecific shRNA; siAPE1, hAPE1-specific siRNA; siNS, nonspecific siRNA; siRNA, small-interfering RNA; SLP, synthetic dipalmitoylated lipoprotein; VEGF, vascular endothelial growth factor.

⁴ The online version of this article contains supplemental material.