Apurinic/apyrimidinic endonuclease 1 is a key modulator of keratinocyte inflammatory responses.
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-1alpha and NF-kappaB, 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-alpha, 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.
Lee
Hye-Mi
HM
Department of Microbiology, College of Medicine, Chungnam National University, Daejeon, South Korea.
Yuk
Jae-Min
JM
Shin
Dong-Min
DM
Yang
Chul-Su
CS
Kim
Kwang-Kyu
KK
Choi
Dae-Kyoung
DK
Liang
Zhe-Long
ZL
Kim
Jin-Man
JM
Jeon
Byeong Hwa
BH
Kim
Chang Deok
CD
Lee
Jeung-Hoon
JH
Jo
Eun-Kyeong
EK
D023181:Antimicrobial Cationic Peptides / Q000276:immunology / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D019938:Cyclin D1 / Q000276:immunology / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000276:immunology / Q000378:metabolism; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000187:drug effects / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D004817:Epidermis / Q000201:enzymology* / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology / Q000378:metabolism; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000276:immunology / Q000378:metabolism; D007249:Inflammation / Q000201:enzymology; D007369:Interferon Inducers / Q000494:pharmacology; D016209:Interleukin-8 / Q000276:immunology / Q000378:metabolism; D015603:Keratinocytes / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D011070:Poly I-C / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology / Q000378:metabolism; D011565:Psoriasis / Q000201:enzymology* / Q000473:pathology; D034741:RNA, Small Interfering / Q000276:immunology / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000276:immunology / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects / Q000276:immunology; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology; D015054:Zymosan / Q000494:pharmacology; D054804:Cathelicidins
D023181:Antimicrobial Cationic Peptides; C530104:CCND1 protein, human; C508606:CXCL8 protein, human; D051793:Hypoxia-Inducible Factor 1; D007369:Interferon Inducers; D016209:Interleukin-8; D016328:NF-kappa B; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha; D019938:Cyclin D1; D015054:Zymosan; D051057:Proto-Oncogene Proteins c-akt; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D048049:Extracellular Signal-Regulated MAP Kinases; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D011070:Poly I-C; D054804:Cathelicidins