Cytokines Tumor Necrosis Factor and Interleukin–6 in Experimental Biliary Obstruction in Mice

Abstract

The putative role of the cytokines interleukin-6 and tumor necrosis factor in the pathophysiology of the complications and mortality after surgery in jaundiced patients was studied in a murine model. Cytokine serum levels were determined in mice with experimental biliary obstruction. As an indicator of the activation status of macrophages, cytokine release by mononuclear phagocytes obtained from such mice was assessed. Following surgery, interleukin-6 levels increased to 2 to 3 ng/ml after 3 to 4 hr, but declined rapidly afterward to levels of 60 pg/ml after 10 days. After 12 days, substantial interleukin-6 levels were observed in jaundiced mice (100 pg/ml), whereas levels in sham mice further decreased (p less than 0.001). The cytokine tumor necrosis factor was frequently present in the serum of jaundiced mice. After 22 days, when killed, all jaundiced mice showed significant tumor necrosis factor levels (p less than 0.001). This was in contrast to sham mice in which tumor necrosis factor was never detected. The presence of an activated state of macrophages in jaundiced mice was concluded from the observed high spontaneous cytokine release and significantly higher release after stimulation (p less than 0.05). The presence of circulating cytokines was discussed in the context of the postoperative complications observed in jaundiced patients.

Interleukin-1 receptor type I gene-deficient bile duct-ligated mice are partially protected against endotoxin

“…23 Recently, IL-6 was reported to be produced in livers of mice subjected to bdl, 24 which is in line with earlier reports of elevated plasma levels of IL-6 in mice with experimentally induced obstructive jaundice. 11,25,26 Similar to the absence of differences between IL-1R ϩ/ϩ and IL-1R Ϫ/Ϫ mice as described here, IL-6 gene-deficient mice did not demonstrate clear phenotypic differences after bdl when compared with wild-type mice. 24 Experimentally induced obstruction of the bile duct was associated with a profoundly increased susceptibility towards endotoxin, as indicated by the occurrence of mortality after administration of endotoxin in a dose that did not cause mortality, enhanced cytokine release, or more severe liver damage in sham-operated mice.…”

Preoperative Biliary Drainage in Patients with Obstructive Jaundice: History and Current Status

“…20,26,[34][35][36][37][38] Mortality was significantly reduced in these animal models. With respect to the preferred route of drainage, internal PBD was found to be superior to external PBD in terms of reduction in endotoxemia and mortality by some, whereas others demonstrated external drainage, although in the shortterm, to lead to a better recovery of cellular immunity than internal drainage.…”

“…[17][18][19][20][21][22] Increased concentrations of TNF, mainly produced by liver Kuppfer cells, or rather, the imbalance with its soluble receptors, as antagonists and released from the cell membrane by endotoxemia, are suggested to contribute to development of complications. 18,23 After endotoxin administration to cholestatic rats, Kennedy et al demonstrated that blockade of Kuppfer cells with gadolinium chloride leads to a lower systemic TNF activity and subsequently resulted in an improved survival.…”

Heme oxygenase-1 overexpression increases liver injury after bile duct ligation in rats

“…Kupffer cells release many mediators that activate stellate cells, including TNF-α, TGF-β, human growth factor, PDGF, and reactive oxygen species [60,70] . TNF-α production and NF-κB activation increase during cholestasis [71,72] . Activation of NF-κB, probably due to oxidative stress, could lead to expression of TNF-α.…”