Role of the innate immune system in animal models of living donor liver transplantation
Final Report Abstract
In living donor liver transplantation (LDLT), the innate immune system plays an important role in regulating the regeneration of the remnant liver and the transplant as well as damaging inflammatory processes (e.g., ischemia/reperfusion injury, rejection, infections) in the transplant, respectively. Since it has been suggested that the Toll-Like-Receptor (TLR)-system may be crucial for these events, we investigate its role in in vitro experiments with isolated primary human and murine liver cells. TLR 1-9 agonists were tested for their ability to induce or suppress pro- or anti-regenerative cytokines and signaling molecules in isolated parenchymal and non-parenchymal liver cells. In addition, the role of corticosteroids that are used for immunosuppression after LDLT was analyzed in this system. TLR1-9 agonists could induce the production of pro- and anti-regenerative mediators including HGF in all three cell types. However, the pattern varied significantly between the individual TLR ligands and cell typeI. Stimulation of TLR1, -2, -4, -7 and -8 induced the expression of a pro-regenerative pattern (IL-6, TGF-α, HGF, TNF-α, no IFNs, no or little TGF-β) in KC, LSEC and hepatocytes, respectively. Stimulation of TLR5, -6 and -9 induced both pro- and anti-regenerative mediators. TLR1, -2, -3, -4, and -8 agonists increased proliferation of hepatocytes. Stimulation of TLR2, -3, -4, -7 and -8 led to activation of pro-regenerative signaling molecules, while an activation of STAT1 can be detected after stimulation with TLR3 and -9 ligands. This led us to suggest that the administration of TLR agonists with favorable ratios of pro- and antiregenerative mediators before liver resection may have a potential to optimize liver regeneration postoperatively. Only little is known about the mechanisms of action of corticosteroids in the immunosuppressive treatment after LDLT. We hypothesized that steroids may interfere with the activation of the TLR system of the liver. TLR agonists induced the expression of pro- (TNF-α, IL-6, IFN-β) and anti-inflammatory cytokines (IL-10, TGF-β), which was differentially modulated by steroid treatment. TNF-α and IL-6 expression was suppressed by dexamethasone while IL-10 but not TGF-β was enhanced after TLR stimulation. Interferonβ production induced by TLR4 agonists but not TLR3 agonists was inhibited by dexamethasone. TLR expression itself was downregulated by steroid treatment in a cell type-specific manner. These effects were associated with suppression of the TLR-mediated activation of NF-κB. We concluded from these experiments that this represents an as yet unknown mechanism of action for corticosteroids which may at least in part explain their immunosuppressive effects after liver transplantationII. This work received the EASL best poster award in 2008.
Publications
- Glycine pretreatment ameliorates liver injury after partial hepatectomy in the rat. J. Invest. Surg. 2010, 23: 12-20
Benkö T, Frede S, Gu Y, Best J, Baba HA, Schlaak JF, de Groot H, Fandrey J, Rauen U
(See online at https://doi.org/10.3109/08941930903469466) - TLR induced innate immune response in non-parenchymal liver cells are cell typespecific. Immunology 2010, 129: 363-374
Wu J, Meng Z, Jiang M, Zhang E, Trippler M, Broering R, Bucchi A, Krux F, Dittmer U, Yang D, Roggendorf M, Gerken G, Lu M, Schlaak JF
(See online at https://doi.org/10.1111/j.1365-2567.2009.03179.x) - Corticosteroids shift the response pattern of the hepatic innate immune system from an inflammatory to an anti-inflammatory state. Int. Immunol. 2011, 23: 537-544
Montag M, Broering R, Min J, Lu M, Sowa J-P, Gerken G, Schlaak JF
(See online at https://doi.org/10.1093/intimm/dxr048)
