A dual regulatory role of apurinic/apyrimidinic endonuclease 1/redox factor-1 in HMGB1-induced inflammatory responses.
Apurinic/apyrimidinic endonuclease 1/Redox factor-1 (APE1) is a multifunctional protein involved in reduction-oxidation regulation. High-mobility group box 1 (HMGB1) is released by necrotic cells and various inflammatory stimuli, acting as an inflammatory marker in sepsis and autoimmune diseases. Here, we report the dual regulatory role of APE1 in inflammatory signaling to extracellular HMGB1 or in the release of endogenous HMGB1 in human monocytes/macrophages. Forced cytoplasmic overexpression of APE1 profoundly attenuated the upregulation of HMGB1-mediated reactive oxygen species generation, cytokine secretion, and cyclooxygenase-2 expression by primary monocytes and macrophage-like THP-1 cell lines. In addition, HMGB1-induced activation of p38 and c-Jun N-terminal kinase (JNK), but not extracellular signal-regulated kinase 1/2, was strongly abrogated by the overexpression of APE1. The activation of apoptosis signal-regulating kinase 1 was required for both the p38 and JNK activation challenge with HMGB1. The extracellular release of HMGB1 by activated macrophages was inhibited by APE1 transfection. Small interfering RNA (siRNA) knockdown of endogenous APE1 impaired HMGB1-mediated cytokine expression and MAPK activation in THP-1 cells. HMGB1 stimulation induced the translocation of APE1 to the nucleus of the cell. In addition, APE1 silencing via siRNA transfection inhibited both the nuclear and cytoplasmic expression of APE1. These data identify APE1 as a novel dual regulator of inflammatory signaling to HMGB1 by human monocytes/macrophages. The modulation of cytosolic APE1 expression might be useful as a potential therapeutic modality for the treatment of inflammatory or autoimmune diseases.
Yuk
Jae-Min
JM
Department of Microbiology, College of Medicine, Chungnam National University, Daejeon, South Korea.
Yang
Chul-Su
CS
Shin
Dong-Min
DM
Kim
Kwang-Kyu
KK
Lee
Sang Ki
SK
Song
Yun Jeong
YJ
Lee
Hye-Mi
HM
Cho
Chung-Hyun
CH
Jeon
Byeong Hwa
BH
Jo
Eun-Kyeong
EK
D001483:Base Sequence; D017931:DNA Primers; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D024243:HMGB1 Protein / Q000502:physiology*; D006801:Humans; D007249:Inflammation / Q000503:physiopathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017931:DNA Primers; D024243:HMGB1 Protein; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase