title: Downregulation of TLR4-dependent ATP production is critical for estrogen-mediated immunoprotection in Kupffer cells following trauma-hemorrhage.
abstract: Toll-like receptor 4 (TLR4) mediates mitochondrial DNA (mtDNA) damage and biogenic responses. Mitochondrial transcription factor A (Tfam) is an essential regulator for mtDNA transcription and ATP production. Increased ATP levels were associated with normalization of immune function following trauma-hemorrhage. Moreover, administration of 17beta-estradiol following trauma-hemorrhage upregulates cardiac Tfam and ATP levels. We therefore hypothesized that the salutary effect of 17beta-estradiol on Kupffer cell function following trauma-hemorrhage is mediated via negative regulation of TLR4, which downregulates iNOS, upregulates Tfam and mtDNA-encoded gene cytochrome c oxidase I (mtCOI), and consequently increases cellular ATP levels. Male C3H/HeN, C3H/HeOuJ (intact TLR4), and C3H/HeJ (TLR4 mutant) mice were subjected to trauma-hemorrhage (mean BP 35 +/- 5 mmHg approximately 90 min, then resuscitation) or sham operation. At the beginning of resuscitation, mice received 17beta-estradiol (25 microg/25 g) or vehicle intravenously and were sacrificed 2 h thereafter. Kupffer cell TLR4, iNOS, IL-6 and TNF-alpha production capacities were increased, and ATP, Tfam, and mtCOI levels were decreased following trauma-hemorrhage. Administration of 17beta-estradiol following trauma-hemorrhage prevented the increase in Kupffer cell TLR4, iNOS, and cytokine production. This was accompanied by normalized ATP, Tfam, and mtCOI levels. Furthermore, the decreased Kupffer cell ATP and mtCOI levels were not observed in TLR4 mutant mice following trauma-hemorrhage. Taken together, these findings suggest that downregulation of TLR4-dependent ATP production is critical to 17beta-estradiol-mediated immunoprotection in Kupffer cells following trauma-hemorrhage.
authors.affiliation: Center for Surgical Research and Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Ya-Ching
authors.initials: YC
authors.lastname: Hsieh
authors.forename: Michael
authors.initials: M
authors.lastname: Frink
authors.forename: Takashi
authors.initials: T
authors.lastname: Kawasaki
authors.forename: Bjoern M
authors.initials: BM
authors.lastname: Thobe
authors.forename: Mashkoor A
authors.initials: MA
authors.lastname: Choudhry
authors.forename: Martin G
authors.initials: MG
authors.lastname: Schwacha
authors.forename: Kirby I
authors.initials: KI
authors.lastname: Bland
authors.forename: Irshad H
authors.initials: IH
authors.lastname: Chaudry
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D003576:Electron Transport Complex IV / Q000235:genetics / Q000378:metabolism; D004958:Estradiol / Q000008:administration & dosage*; D005263:Femoral Artery / Q000601:surgery; D006609:High Mobility Group Proteins / Q000235:genetics / Q000378:metabolism; D007275:Injections, Intravenous; D015850:Interleukin-6 / Q000378:metabolism; D007728:Kupffer Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008822:Mice, Transgenic; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D009154:Mutation; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D012771:Shock, Hemorrhagic / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; D015850:Interleukin-6; C081930:Tfam protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D004958:Estradiol; D012313:RNA; D000255:Adenosine Triphosphate; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D003576:Electron Transport Complex IV