Inhibition of interleukin-6-transsignaling via gp130-Fc in hemorrhagic shock and sepsis.
BACKGROUND
Immune function after hemorrhagic shock and subsequent sepsis is characterized by an early proinflammatory burst of IL-6, and high IL-6 levels have been linked to high mortality after trauma and in sepsis. Trans-signaling is defined as the activation of cells that do not express the membrane bound IL-6 receptor by the complex of IL-6 and the soluble IL-6 receptor (sIL-6R). Gp130-Fc is able to bind the IL-6/sIL-6R complex, and beneficial effects of IL-6 blockade in chronic inflammatory diseases have been shown. The first aim of this study was to investigate the potential effect of a gp130 blockade via the gp130-Fc antibody causing impairment of IL-6 signaling. The second aim was to find out what role the IL-6/sIL-6R complex can play in the context of hemorrhagic shock and subsequent sepsis as an acute inflammatory disease.


METHODS
Male CBA/J mice were subjected to hemorrhagic shock (35+/-5 mmHg for 90min and fluid resuscitation) or sham operation. At resuscitation each animal received either 0.5mg gp130-Fc or placebo (PL) i.p. At 48 h after resuscitation, both splenocytes and peritoneal macrophages (pMphi) were harvested or polymicrobial sepsis was induced by cecal ligation and puncture. Survival over 10 d was determined. Release of IL-6, TNF-alpha, and IL-10 of pMphi and release of IL-2, IL-10, and IFN-gamma of splenocytes was assessed by ELISA. Proliferation of splenocytes and their morphologic damage were determined.


RESULTS
Binding of the IL-6/sIL-6R complex by gp130-Fc led to significant lower IL-6 levels compared with placebo treated animals. Placebo treated males showed depressed proinflammatory immune response (IL-2, IL-6) after hemorrhagic shock. While splenocyte proliferation was significantly reduced directly after hemorrhagic shock and restored after 48 h by gp130-Fc, pMphi cytokine release was not influenced. Finally, survival appeared to be unaffected.


CONCLUSIONS
Transsignaling does not seem to play a pivotal role in the development of the immune dysfunction and mortality in our model of hemorrhage and subsequent sepsis.
Mees
Soeren Torge
ST
Department of General Surgery, University of Muenster, Muenster, Germany. soerentorge.mees@ukmuenster.de
Toellner
Sietje
S
Marx
Kerstin
K
Faendrich
Fred
F
Kallen
Karl Josef
KJ
Schroeder
Joerg
J
Haier
Joerg
J
Kahlke
Volker
V
D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D050822:Cytokine Receptor gp130 / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D007082:Ileum / Q000473:pathology; D007107:Immune System / Q000187:drug effects / Q000502:physiology; D015850:Interleukin-6 / Q000378:metabolism; D007668:Kidney / Q000473:pathology; D008099:Liver / Q000473:pathology; D008168:Lung / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000378:metabolism; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D015846:Monokines / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018805:Sepsis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D012771:Shock, Hemorrhagic / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013154:Spleen / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000093242:Interleukin-6 Inhibitors
D000906:Antibodies; D050822:Cytokine Receptor gp130; D015850:Interleukin-6; D015846:Monokines; D019947:Receptors, Interleukin-6; D000093242:Interleukin-6 Inhibitors