IL-4 Protects the Mitochondria Against TNF alpha and IFN gamma 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 IFN gamma, TNF alpha, 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 TNF alpha, individually and combined with IFN gamma, 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. IFN gamma -/- 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 IFN gamma and TNF alpha levels increase during clearance of infection, the concomitant increase in IL-4 and IL-6 protects mitochondrial function.

Subject headings

NATURVETENSKAP  -- Biologi -- Cellbiologi (hsv//swe)

NATURAL SCIENCES  -- Biological Sciences -- Cell Biology (hsv//eng)

Keyword

tumor-necrosis-factor

murine colonic hyperplasia

pro-inflammatory

cytokines

interferon-gamma

cell-death

respiratory-chain

epithelial-cells

up-regulation

in-vivo

apoptosis

Publication and Content Type

ref (subject category)

art (subject category)