Although anti-IL-6-mAb down-regulates cardiac IL-6 and attenuates IL-6-mediated cardiac dysfunction following trauma-hemorrhage, it is not known whether blockade of IL-6 receptor will down-regulate cardiac IL-6 and improve cardiac function under those conditions. Six groups of male adult rats (275-325 g) were used: sham/trauma-hemorrhage + vehicle, sham/trauma-hemorrhage + IgG, sham/trauma-hemorrhage + anti-rat sIL-6R. Rats underwent trauma-hemorrhage (removal of 60% of the circulating blood volume and fluid resuscitation after 90 min). Vehicle (V), normal goat IgG or anti-rat sIL-6R (16.7 μg/kg BW) was administered intra-peritoneally in the middle of resuscitation. Two hours later, cardiac function was measured by ICG dilution technique; blood samples collected, cardiomyocytes isolated, and cardiomyocyte nuclei were then extracted. Cardiac IL-6, IL-6R, gp130, IκB-α/P-IκB-α, NF-κB, and ICAM-1 expressions were measured by immunoblotting. Plasma IL-6 and cardiomyocyte NF-κB DNA-binding activity were determined by ELISA. In additional animals, heart harvested and cardiac MPO activity and CINC-1 and -3 were also measured. In another group of rats, cardiac function was measure by microspheres at 24 h following trauma-hemorrhage. Cardiac function was depressed and cardiac IL-6, P-IκB-α, NF-κB and its DNA-binding activity, ICAM-1, MPO activity, and CINC-1 and -3 were markedly increased after trauma-hemorrhage. Moreover, cardiac dysfunction was evident even 24 h after trauma-hemorrhage. Administration of sIL-6R following trauma-hemorrhage: (1) improved cardiac output at 2 h and 24 h (p < 0.05); (2) down-regulated both cardiac IL-6 and IL-6R (p < 0.05); and (3) attenuated cardiac P-IκB-α, NF-κB, NF-κB DNA-binding activity, ICAM-1, CINC-1, -3, and MPO activity (p < 0.05). IgG did not significantly influence the above parameters. Thus, IL-6-mediated up-regulation of cardiac NF-κB, ICAM-1, CINC-1, -3, and MPO activity likely contributes to altered cardiac function following trauma-hemorrhage. Since IL-6R blockade after trauma-hemorrhage down-regulates cardiac IL-6 and improves cardiac functions, blockade of IL-6R following trauma-hemorrhage appears to be a novel and effective adjunct for improving organ and cell function under those conditions. © 2006 Elsevier Inc. All rights reserved.