Inhibition of interleukin-6-transsignaling via gp130-Fc in hemorrhagic shock and sepsis
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Inhibition of interleukin-6-transsignaling via gp130-Fc in hemorrhagic shock and sepsis. / Mees, Soeren Torge; Toellner, Sietje; Marx, Kerstin; Faendrich, Fred; Kallen, Karl Josef; Schroeder, Joerg; Haier, Joerg; Kahlke, Volker.
In: J SURG RES, Vol. 157, No. 2, 12.2009, p. 235-42.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Inhibition of interleukin-6-transsignaling via gp130-Fc in hemorrhagic shock and sepsis
AU - Mees, Soeren Torge
AU - Toellner, Sietje
AU - Marx, Kerstin
AU - Faendrich, Fred
AU - Kallen, Karl Josef
AU - Schroeder, Joerg
AU - Haier, Joerg
AU - Kahlke, Volker
PY - 2009/12
Y1 - 2009/12
N2 - 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.MATERIAL AND 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.CONCLUSION: 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.
AB - 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.MATERIAL AND 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.CONCLUSION: 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.
KW - Animals
KW - Antibodies
KW - Cell Proliferation
KW - Cells, Cultured
KW - Cytokine Receptor gp130
KW - Disease Models, Animal
KW - Ileum
KW - Immune System
KW - Interleukin-6
KW - Kidney
KW - Liver
KW - Lung
KW - Macrophages, Peritoneal
KW - Male
KW - Mice
KW - Mice, Inbred CBA
KW - Monokines
KW - Receptors, Interleukin-6
KW - Sepsis
KW - Shock, Hemorrhagic
KW - Signal Transduction
KW - Spleen
U2 - 10.1016/j.jss.2008.08.035
DO - 10.1016/j.jss.2008.08.035
M3 - SCORING: Journal article
C2 - 19589542
VL - 157
SP - 235
EP - 242
JO - J SURG RES
JF - J SURG RES
SN - 0022-4804
IS - 2
ER -