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Cyclosporin A (CsA) is the most common immunosuppressive drug used in organ transplantation. However, the clinical use of CsA is often limited by several side effects including hepatotoxicity. In the present study, it was found that administration of CsA causes a rapid activation of TGF-β/Smad signaling cascade and subsequent expression of the profibrotic genes connective tissue growth factor (CTGF) and tissue inhibitors of matrix metallproteinases-1 (TIMP-1) in rat liver. In addition, Smad phosphorylation and subsequent CTGF and TIMP-1 expression were markedly reduced in the presence of neutralizing monoclonal TGFβ1-3 antibody. Furthermore, CsA administration significantly increased the serum levels of the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST) as well as lipid peroxidation in hepatic tissues. Moreover, significant reduction in the hepatic content of reduced glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) was observed in CsA-alone-treated animals. Histopathological changes were also observed in CsA-alone-treated rats. Pretreatment of animals with Vitamin E (Vit E) before CsA administration significantly reduced TGF-β level as well as Smad phosphorylation and subsequent CTGF and TIMP-1 expression. Furthermore, administration of PEG-SOD clearly attenuated TGF-β/Smad signaling induced by CsA. Moreover, concomitant administration of Vit E along with CsA significantly ameliorated the histopathological changes and improved liver function as well as the antioxidant capacity. Finally, this study shows that the immunosuppressive efficiency of CsA was not altered in the presence of Vit E. These data may support the concept of using antioxidant therapy as a valuable approach for the prevention of CsA-induced tissue fibrosis.

Viral hepatitis-induced oxidative stress accompanied by increased levels of transforming growth factor-β (TGF-β) and hepatic fibrosis are hallmarks of hepatitis C virus infection. The present study was designed to investigate the potential protective effect of propolis against liver injury induced by concanavalin A (Con A), a T-cell-dependent model that causes an immune-mediated hepatitis in a similar pattern to the one induced by viral infections. In the present study, rats were randomly divided into four groups. The first group (control) was administered the vehicle of Con A (i.v.) for 24 h. The second group received Con A (12 mg/kg body weight i.v.) for 24 h. The third group received propolis (300 mg/kg by oral gavage) 5 days before and concurrently with Con A for 24 h. The last group received propolis alone. Following a single injection of Con A, histopathological changes as well as significant reduction in albumin level were observed. In addition, serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin were significantly increased. These increases correlated with an increase in lipid peroxidation and downregulation of reduced glutathione (GSH) as well as superoxide dismutase (SOD) and catalase activities in liver tissue. Furthermore, these changes were associated with an increase in serum levels of the inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) as well as the profibrotic cytokine TGF-β. Moreover, TGF- β activation was accompanied with an increase in Smad phosphorylation. Interestingly, concomitant administration of propolis along with Con A significantly attenuated all these negative effects and improved liver function indicating that propolis has the ability to protect rats from Con A-induced hepatitis.

Several animal studies suggest a role of platelet-derived growth factors (PDGFs) particularly A and B in atherosclerosis. Previously, it has been shown that viral infections have the ability to initiate and accelerate atherosclerosis in animal models. Recently, it has been reported that IL-18 has a pro-atherogenic character. Moreover, viral infections have been shown to be associated with induction of IL-18 bioactivity. By using human predendritic KG1 cells, we sought to assess PDGF-AA production under the influence of IL-18 and the byproduct of viral replication, dsRNA-mimetic poly (I:C). Here we demonstrate that poly (I:C) and IL-18 have the ability to induce PDGF-AA expression. In addition, costimulation of KG-1 cells with both IL-18 plus poly (I:C) shows an additive effect on PDGF-AA production. Furthermore, we demonstrate that neither p38 nor SAPK/JNK is required for PDGF-AA production by both PIC and IL-18. However, the expression of PDGF-AA has been found to be associated with increased activation of NF-κB and enhancement of DNA-binding capacity of NF-κB as shown by electrophoretic mobility shift assay (EMSA) and supershift analysis. Collectively, this study demonstrates that the byproduct of viral replication, dsRNA [poly (I:C)], and IL-18 have the ability to induce PDGF-AA in NF-κB-dependent manner. Furthermore, dsRNA act in an additive way with IL-18 to induce PDGF-AA which plays a major role in atherosclerosis. These data might help to understand the pro-atherogenic character of IL-18 and molecular mechanisms of viral infection-induced atherosclerosis.

Interleukin (IL)-18 bioactivity and dsRNA sensing by receptors of innate immunity are key components of anti-viral host defense. Despite extensive data on signal transduction activated by both pathways knowledge on cross-communication is incomplete. By using human PBMC and predendritic KG1 cells, as prototypic IL-18-responsive cellular models, we sought to assess cytokine production under the influence of IL-18 and the dsRNA-mimetic poly (I:C). Here, we report on potent synergy between both mediators concerning pro-inflammatory IFNgamma and TNFalpha production. KG1 data revealed that synergistic induction likely relied on TLR3 and was associated with prolonged/increased activation of NF-kappaB, as detected by IkappaB analysis and luciferase reporter assays, respectively. Moreover, extended activation of JNK was mediated by IL-18/poly (I:C). Although vital for innate immunity, overwhelming induction of inflammatory cytokines during viral infections poses the threat of serious collateral tissue damage. The stunning synergism inherent to IL-18/dsRNA-induced TNFalpha/IFNgamma detected herein may contribute to this pathological phenomenon.