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

Abstract 

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.

Abbreviations: TNF-α, tumor necrosis factor-α, IL-1β, interleukin-1β, IL-6, interleukin-6, WT, wild type, KO, IL-6 knockout, MO, month-old, B+S, burn complicated by sepsis, TBSA, total body surface area, STAT-3, signal transducer and activator of transcription 3, p-STAT-3, phosphorylated signal transducer and activator of transcription 3, HR, heart rate, MAP, mean arterial pressure, SV, stroke volume, CO, cardiac output, SVR, systemic vascular resistance, ESPVR, systolic pressure–volume relationship, PRSW, preload-recruitable stroke work, E_max, maximum elastance, IVC, inferior vena cava

Keywords: Interleukin-6, Cytokines, Burn, Sepsis, Heart, Aging