The Role of Kupffer Cells and TNF-alpha in Monocrotaline and Bacterial Lipopolysaccharide-Induced Liver Injury

Abstract

Coexposure to small, noninjurious doses of the pyrrolizidine alkaloid phytotoxin monocrotaline (MCT) and bacterial lipopolysaccharide (LPS) results in synergistic hepatotoxicity. Both centrilobular and midzonal liver lesions occur and are similar to those seen from large, toxic doses of MCT and LPS, respectively. The nature of the lesions in vivo and results from studies in vitro suggest that injury is mediated indirectly rather than from a simple interaction of MCT and LPS with hepatic parenchymal cells. Accordingly, the role of inflammatory factors, such as Kupffer cells and TNF-alpha, in the development of MCT/LPS-induced liver injury was investigated. In Sprague-Dawley rats, MCT (100 mg/kg, i.p.) was administered 4 h before LPS (7.4 x 10(6) EU/kg, i.v.). Pretreatment of these animals with gadolinium chloride, an inhibitor of Kupffer cell function, attenuated liver injury 18 h after MCT administration. An increase in plasma TNF-alpha preceded the onset of hepatic parenchymal cell injury, raising the possibility that this inflammatory cytokine contributes to toxicity. Either pentoxifylline, an inhibitor of cellular TNF-alpha synthesis, or anti-TNF-alpha serum coadministered to MCT/LPS-treated animals significantly attenuated liver injury. These results suggest that Kupffer cells and TNF-alpha are important mediators in the synergistic hepatotoxicity resulting from MCT and LPS coexposure.

The Phosphatidylinositol 3-Kinase/Protein Kinase B Signaling Pathway Is Activated by Lipoteichoic Acid and Plays a Role in Kupffer Cell Production of Interleukin-6 (IL-6) and IL-10

“…The mechanisms balancing the levels and time courses of pro-versus anti-inflammatory mediators in tissue macrophages are only beginning to be understood and can best be worked out through comparative studies of various combinations of cytokines produced from the same cell source in the infected tissue. Kupffer cells are important producers of TNF-␣, IL-10, and IL-6 in vivo, and the balance in the levels of these cytokines is not only essential for immune responses locally in the liver but may also alter systemic levels of pro-and anti-inflammatory cytokines (11,13,25,43,56). IL-10 has the ability to suppress proinflammatory cytokine release and may protect against the onset of irreversible sepsis (28), and hence, the initial local TNF-␣-IL-10 balance is crucial for further development of the inflammatory process.…”

“…It was also recently reported that an early rise in IL-6 and IL-10 occurred in plasma during liver surgery, whereas the level of the proinflammatory cytokine TNF-␣ remained low (21). In a bacterial infection, however, Kupffer cells produce significant amounts of TNF-␣ (4,51,55,56). In infections by gram-negative organisms, lipopolysaccharide (LPS) is the main initiator of inflammatory reactions that may lead to circulatory failure and organ injury.…”

Inflammatory Stress and Idiosyncratic Hepatotoxicity: Hints from Animal Models

“…Pentoxifylline is a methylxanthine that inhibits the synthesis of TNF␣ (Dezube et al, 1993;Yee et al, 2003a), but it also has several other pharmacological effects (Banfi et al, 2004). Etanercept is a dimeric fusion protein that contains a soluble TNF␣ receptor capable of selectively neutralizing TNF␣ in serum.…”

Kupffer cell-mediated hepatic injury induced by silica nanoparticles in vitro and in vivo

“…24 Furthermore, a previous study has shown that KCs participate in monocrotaline/ lipopolysaccharide-induced liver injury through the release of inflammatory cytokines, such as tumor necrosis factor (TNF)-α. 25 These studies suggest that KCs are activated by foreign stimuli and release a variety of bioactive mediators, which fulfill a crucial function in the response to liver injury. However, there have been few relevant reports addressing whether KCs can be activated to release these bioactive substances and mediate hepatic injury after phagocytosis of SiO 2 NPs, which is essential to understanding the mechanism underlying hepatotoxicity induced by SiO 2 NPs.…”