Role of Janus kinase/signal transducer and activator of transcription pathway in regulation of expression and inflammation-promoting activity of high mobility group box protein 1 in rat peritoneal macrophages.
Signal transduction mechanism in the regulation of high mobility group box protein 1 (HMGB1) has not yet been well elucidated. Our data showed for the first time that Janus kinase-signal transduction and activator of transcription (JAK/STAT) pathway played a major role in the regulation of expression and inflammatory effect of HMGB1. The study was carried out in the following sequence. Firstly, the role of JAK/STAT pathway in the regulation of expression of HMGB1 was examined. After stimulation with 75 ng/mL LPS in vitro, significant increases in HMGB1 expression and prompt activation of JAK/STAT pathway were demonstrated in cultured macrophages. On the other hand, administration of AG490 (specific inhibitor for JAK2), fludarabine (specific inhibitor for STAT1) or rapamycin (specific inhibitor for STAT3) markedly suppressed HMGB1 expression. Secondly, the role of JAK/STAT pathway in the regulation of TNF-alpha expression induced by HMGB1 was examined. When macrophages were stimulated with 10 microg/mL HMGB1 in vitro, significant increases in TNF-alpha expression and prompt activation of JAK/STAT pathway were demonstrated, whereas inhibitors of JAK/STAT pathway significantly suppressed TNF-alpha expression. Taken together, our data strongly indicated that expression and inflammatory effect of HMGB1 could be mediated by JAK/STAT pathway and suggested a possible clinical strategy to control an inflammatory effect of HMGB1 in sepsis.
Liu
Hui
H
Department of Microbiology and Immunology, Burns Institute, First Hospital Affiliated to PLA General Hospital (formerly 304th Hospital), Beijing 100037, People's Republic of China.
Yao
Yong-Ming
YM
Yu
Yan
Y
Dong
Ning
N
Yin
Hui-Nan
HN
Sheng
Zhi-Yong
ZY
D000818:Animals; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000502:physiology; D024243:HMGB1 Protein / Q000096:biosynthesis / Q000235:genetics*; D018836:Inflammation Mediators / Q000502:physiology*; D053613:Janus Kinase 1 / Q000502:physiology*; D008070:Lipopolysaccharides / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000201:enzymology* / Q000276:immunology; D008297:Male; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D050791:STAT Transcription Factors / Q000502:physiology*
D024243:HMGB1 Protein; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D050791:STAT Transcription Factors; C507906:Jak1 protein, rat; D053613:Janus Kinase 1