IL-6 knock-out mice exhibit resistance to splanchnic artery occlusion shock

Abstract

We used IL-6 knock-out (KO) mice to evaluate a possible role for IL-6 in the pathogenesis of splanchnic artery occlusion shock (SAO). SAO shock was induced by clamping both the superior mesenteric artery and the celiac trunk, followed by release of the clamp. There was a marked increase in the peroxynitrite formation in the plasma of the SAO-shocked IL-6 wild-type (WT) mice after reperfusion. Immunohistochemical examination demonstrated a marked increase in the immunoreactivity to nitrotyrosine in the necrotic ileum in shocked IL-6 WT mice. SAO-shocked WT mice developed a significant increase of tissue myeloperoxidase (MPO) and malondialdehyde (MDA) activity and marked histological injury to the distal ileum. SAO shock was also associated with a significant mortality (0% survival). Reperfused ileum tissue sections from SAO-shocked WT mice showed positive staining for P-selectin. Little specific staining was observed in sham-WT mice. Staining of ileum tissue obtained from sham-operated WT mice with anti-ICAM-1 antibody showed weak but diffuse staining, demonstrating that ICAM-1 is constitutively expressed. However, after SAO shock the staining intensity increased substantially in the ileum section from WT mice. Intensity and degree of Pselectin and ICAM-1 were markedly reduced in tissue section from SAO-shocked IL-6 KO mice. SAO-shocked IL-6 KO mice also show significant reduction of neutrophil infiltration into the reperfused intestine, as evidenced by reduced MPO activity, improved histological status of the reperfused tissues, reduced peroxynitrite formation, reduced MDA levels, and improved survival. In vivo treatment with anti-IL-6 significantly prevents the inflammatory process. Our results clearly demonstrate that IL-6 plays an important role in ischemia and reperfusion injury and allows the hypothesis that inhibition of IL-6 may represent a novel and possible strategy. Part of this effect may be due to inhibition of the expression of adhesion molecules and subsequent reduction of neutrophil-mediated cellular injury. J. Leukoc. Biol. 66: 471-480; 1999.

Maladaptive Role of IL-6 in Ischemic Acute Renal Failure

“…These include stimulation of neutrophil release from the bone marrow (32), prevention of neutrophil apoptosis (33), activation of neutrophils to produce toxic enzymes (34), and activation of endothelial cells to express intercellular adhesion molecule 1 and chemokines (35,36). These effects of IL-6 are confirmed by the decreased inflammatory response in transgenic knockout mice after ischemia in the lung (37), gut (7,38), or brain (6); after injections of sterile turpentine (39) or carrageen (35); and after infections. (40,41).…”

IL-6 is essential for development of gut barrier dysfunction after hemorrhagic shock and resuscitation in mice

“…For example, Cuzzocrea et al (8) reported that gut mucosal inflammation and histological damage were markedly attenuated in IL-6 Ϫ/Ϫ compared with IL-6 ϩ/ϩ mice subjected to splanchnic artery occlusion and reperfusion. In another study (9), the same laboratory showed that intestinal inflammation induced by intraperitoneal administration of zymosan was decreased in IL-6 Ϫ/Ϫ compared with IL-6 ϩ/ϩ mice.…”

Temporal Gene Expression Profiling Indicates Early Up-regulation of Interleukin-6 in Isoproterenol-induced Myocardial Necrosis in Rat

“…Importantly, these 2 pathways are overrepresented at 3 hours, subsequent to the spike of Il6 at 1 to 3 hours, supporting the hypothesis that Il6 up-regulation is an early and important phenomenon in isoproterenol-induced cardiotoxicity. However, other genes reported to have important roles in acute myocardial The data represent the mean fold difference of isoproterenol-treated rats (n = 4-5/timepoint) compared to water-treated rats (n = 3 rats/time point Indeed, the effects of Il6 on myocardial function are still under debate: several lines of evidence suggest that Il6 has detrimental effects on the damaged heart, because animals injected with anti-Il6 antibodies have reduced inflammation in several models of ischemia (Cuzzocrea et al, 1999;Kukielka et al, 1995) and Il6-KO mice have fewer histologic lesions and/or better survival than wild-type mice in some inflammatory models (Cuzzocrea et al, 1999;Eriksson et al, 2003). Yet, other studies support a protective function of Il6 in the myocardium, because cardiomyocyte-restricted Il6-KO mice are more susceptible to myocardial injury caused by doxorubicin or lipopolysaccharides (Jacoby et al, 2003) and because mediators that, similarly to Il6, bind to Il6st favor cardiomyocyte hypertrophy and survival (Yasukawa et al, 2001).…”