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Bacterial endotoxin stimulates macrophages to release HMGB1 partly through CD14‐ and TNF‐dependent mechanisms
Author(s) -
Chen Guoqian,
Li Jianhua,
Ochani Mahendar,
RendonMitchell Beatriz,
Qiang Xiaoling,
Susarla Seenu,
Ulloa Luis,
Yang Huan,
Fan Saijun,
Goyert Sanna M.,
Wang Ping,
Tracey Kevin J.,
Sama Andrew E.,
Wang Haichao
Publication year - 2004
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.0404242
Subject(s) - hmgb1 , cd14 , mapk/erk pathway , tumor necrosis factor alpha , lipopolysaccharide , p38 mitogen activated protein kinases , biology , proinflammatory cytokine , tlr4 , kinase , protein kinase a , microbiology and biotechnology , extracellular , cytokine , signal transduction , immunology , inflammation , immune system
Bacterial endotoxin [lipopolysaccharide (LPS)] stimulates macrophages to sequentially release early [tumor necrosis factor (TNF)] and late [high mobility group box 1 (HMGB1)] proinflammatory cytokines. The requirement of CD14 and mitogen‐activated protein kinases [MAPK; e.g., p38 and extracellular signal‐regulated kinase (ERK)1/2] for endotoxin‐induced TNF production has been demonstrated previously, but little is known about their involvement in endotoxin‐mediated HMGB1 release. Here, we demonstrated that genetic disruption of CD14 expression abrogated LPS‐induced TNF production but only partially attenuated LPS‐induced HMGB1 release in cultures of primary murine peritoneal macrophages. Pharmacological suppression of p38 or ERK1/2 MAPK with specific inhibitors (SB203580, SB202190, U0126, or PD98059) significantly attenuated LPS‐induced TNF production but failed to inhibit LPS‐induced HMGB1 release. Consistently, an endogenous, immunosuppressive molecule, spermine, failed to inhibit LPS‐induced activation of p38 MAPK and yet, still significantly attenuated LPS‐mediated HMGB1 release. Direct suppression of TNF activity with neutralizing antibodies or genetic disruption of TNF expression partially attenuated HMGB1 release from macrophages induced by LPS at lower concentrations (e.g., 10 ng/ml). Taken together, these data suggest that LPS stimulates macrophages to release HMGB1 partly through CD14‐ and TNF‐dependent mechanisms.