Anti-rat soluble IL-6 receptor antibody down-regulates cardiac IL-6 and improves cardiac function following trauma-hemorrhage.
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 microg/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, IkappaB-alpha/P-IkappaB-alpha, NF-kappaB, and ICAM-1 expressions were measured by immunoblotting. Plasma IL-6 and cardiomyocyte NF-kappaB 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-IkappaB-alpha, NF-kappaB 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-IkappaB-alpha, NF-kappaB, NF-kappaB 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-kappaB, 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.
Yang
Shaolong
S
Center for Surgical Research and Department of Surgery, The University of Alabama at Birmingham, Birmingham, AL 35294-0019, USA.
Hu
Shunhua
S
Choudhry
Mashkoor A
MA
Rue
Loring W
LW
Bland
Kirby I
KI
Chaudry
Irshad H
IH
D000818:Animals; D000906:Antibodies / Q000276:immunology*; D054360:Chemokine CXCL1; D019743:Chemokines, CXC / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D006321:Heart / Q000502:physiology*; D006470:Hemorrhage / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051550:I-kappa B Kinase / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019947:Receptors, Interleukin-6 / Q000276:immunology* / Q000378:metabolism*; D012039:Regional Blood Flow; D012769:Shock / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors
D000906:Antibodies; D054360:Chemokine CXCL1; D019743:Chemokines, CXC; C513297:Cxcl1 protein, rat; C513294:Cxcl3 protein, rat; D015850:Interleukin-6; D016328:NF-kappa B; D019947:Receptors, Interleukin-6; D018799:Intercellular Adhesion Molecule-1; D009195:Peroxidase; D051550:I-kappa B Kinase