Bacterial endotoxin stimulates macrophages to release HMGB1 partly through CD14- and TNF-dependent mechanisms
| Autor: | Andrew E. Sama, Huan Yang, Seenu Susarla, Mahendar Ochani, Jianhua Li, Ping Wang, Haichao Wang, Luis Ulloa, Saijun Fan, Guoqian Chen, Xiaoling Qiang, Beatriz Rendon-Mitchell, Sanna M. Goyert, Kevin J. Tracey |
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| Rok vydání: | 2004 |
| Předmět: |
Lipopolysaccharides
Male MAPK/ERK pathway Lipopolysaccharide p38 mitogen-activated protein kinases CD14 Immunology Lipopolysaccharide Receptors chemical and pharmacologic phenomena Biology HMGB1 p38 Mitogen-Activated Protein Kinases Antibodies Cell Line Proinflammatory cytokine Mice chemistry.chemical_compound Animals Immunology and Allergy Enzyme Inhibitors HMGB1 Protein Mice Knockout Mitogen-Activated Protein Kinase 3 Dose-Response Relationship Drug Tumor Necrosis Factor-alpha Kinase Macrophages Cell Biology Molecular biology Endotoxemia Mice Inbred C57BL chemistry biology.protein Female Spermine Tumor necrosis factor alpha Immunosuppressive Agents |
| Zdroj: | Journal of Leukocyte Biology. 76:994-1001 |
| ISSN: | 1938-3673 0741-5400 |
| DOI: | 10.1189/jlb.0404242 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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