Mechanism of IL-6-mediated cardiac dysfunction following trauma-hemorrhage

Cardiac function is depressed and circulating IL-6 levels increase following trauma-hemorrhage (T-H). Although sustained elevated IL-6 after T-H correlate with poor outcome, the mechanism by which IL-6 produces cardiac dysfunction remains unknown. We hypothesized that IL-6-mediated cardiac depression is due to upregulation of NF-кB, ICAM, CINC and neutrophil infiltration. Six groups of male adult rats (275–300 g) were used: sham/T-H + vehicle, sham/T-H + IgG, sham/T-H + anti-IL-6mAb. Following midline laparotomy, 60% of the circulating blood was withdrawn and after 90 min, crystalloid fluid resuscitation was provided. Either normal goat IgG or anti-rat IL-6mAb (16.7 μg/kg BW) was administered intraperitoneally at 30 min after the onset of resuscitation. Two hours after resuscitation, cardiac function was measured, blood samples collected, cardiomyocytes isolated and intracellular IL-6 levels measured by flow cytometry. Cardiac IL-6, IL-6R, gp130, NF-кB, IкB-α, and ICAM-1 protein levels were measured in freshly isolated hearts by immunoblotting. Moreover, cardiac MPO activity and CINC-1 and -3 were measured. Cardiac function was depressed and cardiac IL-6, NF-кB, ICAM-1, MPO activity, and CINC-1 and -3 were markedly increased after T-H. Administration of anti-IL-6mAb following T-H: 1) improved cardiac output (P < 0.05); 2) downregulated cardiac IL-6 levels (P < 0.05); 3) attenuated cardiac NF-кB, ICAM-1, CINC-1, -3, and MPO activity (P < 0.05). Administration of IgG, however, did not significantly influence these parameters. Thus, IL-6-mediated upregulation of cardiac NF-кB, ICAM-1, CINC-1, -3, and MPO activity likely contributes to altered cardiac function following T-H and neutralization of IL-6 therefore appears to be an effective and novel adjunct for improving organ/cell function under those conditions.