IL-4 Protects the Mitochondria Against TNFα and IFNγ Induced Insult During Clearance of Infection with Citrobacter rodentium and Escherichia coli.
Citrobacter rodentium is a murine pathogen that serves as a model for enteropathogenic Escherichia coli. C. rodentium infection reduced the quantity and activity of mitochondrial respiratory complexes I and IV, as well as phosphorylation capacity, mitochondrial transmembrane potential and ATP generation at day 10, 14 and 19 post infection. Cytokine mRNA quantification showed increased levels of IFNγ, TNFα, IL-4, IL-6, and IL-12 during infection. The effects of adding these cytokines, C. rodentium and E. coli were hence elucidated using an in vitro colonic mucosa. Both infection and TNFα, individually and combined with IFNγ, decreased complex I and IV enzyme levels and mitochondrial function. However, IL-4 reversed these effects, and IL-6 protected against loss of complex IV. Both in vivo and in vitro, the dysfunction appeared caused by nitric oxide-generation, and was alleviated by an antioxidant targeting mitochondria. IFNγ -/- mice, containing a similar pathogen burden but higher IL-4 and IL-6, displayed no loss of any of the four complexes. Thus, the cytokine environment appears to be a more important determinant of mitochondrial function than direct actions of the pathogen. As IFNγ and TNFα levels increase during clearance of infection, the concomitant increase in IL-4 and IL-6 protects mitochondrial function.
Department of Medical Biochemistry and Cell Biology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Arpan K
AK
Maiti
Department of Medical Biochemistry and Cell Biology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Sinan
S
Sharba
Department of Medical Biochemistry and Cell Biology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Nazanin
N
Navabi
Department of Rheumatology and Inflammation Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Huamei
H
Forsman
Department of Medical Biochemistry and Cell Biology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Harvey R
HR
Fernandez
Department of Medical Biochemistry and Cell Biology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Sara K
SK
Lindén
D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death; D044082:Citrobacter rodentium; D003092:Colitis / Q000235:genetics / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D004756:Enterobacteriaceae Infections / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology* / Q000473:pathology; D004789:Enzyme Activation; D004926:Escherichia coli; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D015847:Interleukin-4 / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010766:Phosphorylation; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D014451:Ubiquinone / Q000031:analogs & derivatives / Q000494:pharmacology
D016207:Cytokines; D045222:Electron Transport Chain Complex Proteins; D009943:Organophosphorus Compounds; D014409:Tumor Necrosis Factor-alpha; D014451:Ubiquinone; D015847:Interleukin-4; D009569:Nitric Oxide; C429014:mitoquinone; D007371:Interferon-gamma; D000255:Adenosine Triphosphate; D053148:Caspase 3