IFN-γ induces high mobility group box 1 protein release partly through a TNF-dependent mechanism
| Autor: | Andrew E. Sama, Haichao Wang, Robert A. Mitchell, Guoqian Chen, Huan Yang, Kevin J. Tracey, Seenu Susarla, Hong Wang, Jialian Han, Christopher J. Czura, Beatriz Rendon-Mitchell, Mahendar Ochani, Jianhua Li |
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| Předmět: |
Male
medicine.medical_treatment Immunology chemical and pharmacologic phenomena HMGB1 Systemic inflammation Cell Line Interferon-gamma Mice medicine Animals Humans Immunology and Allergy HMGB1 Protein Phosphorylation Cells Cultured Mice Knockout Mice Inbred C3H Janus kinase 2 biology Tumor Necrosis Factor-alpha Cell biology DNA-Binding Proteins Mice Inbred C57BL STAT1 Transcription Factor Cytokine Macrophages Peritoneal Trans-Activators biology.protein Cytokines Tumor necrosis factor alpha Macrophage migration inhibitory factor Inflammation Mediators Mitogen-Activated Protein Kinases Signal transduction medicine.symptom Janus kinase |
| Zdroj: | Scopus-Elsevier |
| Popis: | We recently discovered that a ubiquitous protein, high mobility group box 1 protein (HMGB1), is released by activated macrophages, and functions as a late mediator of lethal systemic inflammation. To elucidate mechanisms underlying the regulation of HMGB1 release, we examined the roles of other cytokines in induction of HMGB1 release in macrophage cell cultures. Macrophage migration inhibitory factor, macrophage-inflammatory protein 1β, and IL-6 each failed to significantly induce the release of HMGB1 even at supraphysiological levels (up to 200 ng/ml). IFN-γ, an immunoregulatory cytokine known to mediate the innate immune response, dose-dependently induced the release of HMGB1, TNF, and NO, but not other cytokines such as IL-1α, IL-1β, or IL-6. Pharmacological suppression of TNF activity with neutralizing Abs, or genetic disruption of TNF expression (TNF knockout) partially (50–60%) inhibited IFN-γ-mediated HMGB1 release. AG490, a specific inhibitor for Janus kinase 2 of the IFN-γ signaling pathway, dose-dependently attenuated IFN-γ-induced HMGB1 release. These data suggest that IFN-γ plays an important role in the regulation of HMGB1 release through a TNF- and Janus kinase 2-dependent mechanism. |
| Databáze: | OpenAIRE |
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