IFN-gamma induces high mobility group box 1 protein release partly through a TNF-dependent mechanism.
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 1beta, and IL-6 each failed to significantly induce the release of HMGB1 even at supraphysiological levels (up to 200 ng/ml). IFN-gamma, 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-1alpha, IL-1beta, or IL-6. Pharmacological suppression of TNF activity with neutralizing Abs, or genetic disruption of TNF expression (TNF knockout) partially (50-60%) inhibited IFN-gamma-mediated HMGB1 release. AG490, a specific inhibitor for Janus kinase 2 of the IFN-gamma signaling pathway, dose-dependently attenuated IFN-gamma-induced HMGB1 release. These data suggest that IFN-gamma plays an important role in the regulation of HMGB1 release through a TNF- and Janus kinase 2-dependent mechanism.
Rendon-Mitchell
Beatriz
B
Center of Immunology and Inflammation, North Shore-Long Island Jewish Research Institute, Manhasset, NY 11030, USA.
Ochani
Mahendar
M
Li
Jianhua
J
Han
Jialian
J
Wang
Hong
H
Yang
Huan
H
Susarla
Seenu
S
Czura
Christopher
C
Mitchell
Robert A
RA
Chen
Guoqian
G
Sama
Andrew E
AE
Tracey
Kevin J
KJ
Wang
Haichao
H
D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism; D024243:HMGB1 Protein / Q000378:metabolism*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology; D007371:Interferon-gamma / Q000502:physiology*; D017737:Macrophages, Peritoneal / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D050794:STAT1 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D016207:Cytokines; D004268:DNA-Binding Proteins; D024243:HMGB1 Protein; D018836:Inflammation Mediators; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D020928:Mitogen-Activated Protein Kinases