Age-dependent differences of interleukin-6 activity in cardiac function after burn complicated by sepsis☆

Interleukin (IL)-6 is a pleiotropic cytokine that is activated after acute injuries, and plays an important role during aging. We aim to define the role of IL-6 on myocardial dysfunction following a 40% total body surface area burn followed by late (7 days) Streptococcus pneumoniae sepsis (burn plus sepsis) in 2- and 14-month-old wild type and IL-6−/− mice. We measured global hemodynamic and cardiac contractile function with left ventricular pressure–volume analysis 24h after sepsis induction, and measured phosphorylated signal transducer and activator of transcription 3 (p-STAT-3), tumor necrosis factor (TNF)-α, and IL-1β in the heart with Western blot analysis. We also measured mRNA expression of IL-6, TNF-α, and IL-1β. Sham injured mice did not manifest any appreciable level of p-STAT-3 or functional deficiencies regardless of age or presence of the IL-6 gene. Burn plus sepsis injury was associated with a significant deterioration of global hemodynamic and cardiac contractile function in WT mice in both age groups. This dysfunction was attenuated by IL-6 deficiency at age 2 months, but accentuated at age 14 months. Aging was associated with an increase in mRNA expression of IL-6 (WT mice), TNF-α, and IL-1β (all mice). At age 14 months, IL-6 deficient mice exhibited a greater TNF-α mRNA expression than the wild type mice. We conclude aging is associated with changed cytokine gene transcription, and burn plus sepsis injury further intensifies such gene responses. IL-6 deficiency does not abrogate STAT-3 phosphorylation and it may enhance expression of other inflammatory cytokines. The differential effects of IL-6 deficiency on the cardiac function in young and aging mice cannot be explained by cytokine gene expression alone, and require further studies.