We employ a structural global VAR model to analyze whether U.S. unconventional monetary policy shocks, identified through changes in the central bank’s balance sheet, have an impact on financial and economic conditions in emerging market economies (EMEs). Moreover, we study whether international capital flows are an important channel of shock transmission. We find that an expansionary policy shock significantly increases portfolio flows from the U.S. to EMEs for almost two quarters, accompanied by a persistent movement in real and financial variables in recipient countries. Moreover, EMEs on average respond to the shock with an easing of their own monetary policy stance. The findings appear to be independent of heterogeneous country characteristics like the underlying exchange rate arrangement, the quality of institutions, or the degree of financial openness.

Background: Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine which has been implicated in inflammatory diseases.Chronic inflammation also critically contributes to liver fibrosis.But the specific role of MIF in liver fibrosis has not yet been investigated.In our experiments we uncover an unexpected anti-fibrotic role of MIF in two independent fibrosis models in vivo and in vitro.Methods: Liver fibrosis was induced by CCl 4 or TAA (both 6 weeks) in Mif -/-, Cd74 -/-mice and wild-type mice.Fibrosis was analyzed by histology (sirius red staining), hydroxyproline content and intrahepatic mRNA expression of fibrosis-related genes (Col1a1, Timp1, Tgfb1 and Mmp2) in liver samples.In vitro, the effects of MIF on the proliferation (BrdU assay) and migration (Boyden chamber) of platelet-derived growth factor (PDGF)-stimulated stellate cells were analyzed and the role of AMPK and CD74 was evaluated in cell culture.Results: Constitutive MIF knockout mice (Mif -/-) unexpectedly presented a significantly increased degree of fibrosis as assessed by liver histology and hydroxyproline content in both models of chronic liver injury (CCl 4 and TAA).Pronounced liver fibrosis in Mif -/-mice was associated with strong alterations in fibrosisrelevant genes like Col1a1, Timp1, Mmp2 and Tgfb1.Recombinant Mif alone had no obvious effects on the migration or proliferation of stellate cells, but it strongly inhibited Pdgf-induced migration and proliferation of these cells.The inhibitory effects of Mif were mediated by CD74, which we detected as the most abundant MIF receptor on stellate cells.Recombinant Mif led to the phosphorylation of AMP-activated protein kinase (AMPK) in stellate cells.This mechanism was the basis for the inhibition of Pdgfinduced stellate cell activation by Mif, as shown by AMPK-specific inhibition.The crucial role of CD74 in MIF-mediated anti-fibrotic properties is further supported by augmented liver scarring in Cd74 -/-mice in vivo as assessed by histology and hepatic hydroxyproline content.Conclusions: We describe a novel and previously unexpected antifibrotic function of MIF which is mediated through CD74 and increased AMPK phosphorylation in stellate cells.These data imply MIF and its receptor CD74 as new targets for the treatment of fibrotic liver diseases.

Aims: Macrophage migration inhibitory factor (MIF) is a pleiotropic chemokine-like inflammatory cytokine which has been implicated in various chronic inflammatory diseases. Although a contribution of MIF is proposed during liver injury, its role during chronic liver injury and hepatic fibrogenesis has not yet been systematically investigated. Therefore, we compared MIF–/– with wild-type mice in two independent models of experimental liver fibrosis.

POSTERSrespectively.Cell survival was assayed by cytotoxicity assays and the expression of c-Jun and its potential target genes was analyzed.Results: Chemical induction of ER stress resulted in a rapid and robust expression of c-Jun in both, human hepatoma cells and mouse primary hepatocytes, but surprisingly, no major differences in ER stress-mediated cell death were observed in cells lacking c-Jun.However, massive cytoplasmic vacuolization occurred upon ER stress in primary knock-out hepatocytes, most likely due to expansion of the ER.A similar phenotype was observed in primary hepatocytes in which Jun N-terminal kinases, important regulators of c-Jun activity, were inhibited pharmacologically.This vacuolization correlated with increased expression of ER stress marker genes such as gadd153, bip and spliced xbp-1 and subsequent expression of several chemokines including CXCL1 and CXCL2.Recent findings suggest that ER expansion is tightly controlled by self-degradation of these organelles in a process called autophagy.Interestingly, autophagy appeared to be impaired in the absence of c-Jun.Conclusions: These findings suggest that c-Jun, although not essential for hepatocyte survival, tightly controls the hepatocellular response to ER stress possibly by interacting with the autophagy machinery.

Liver fibrosis is a wound healing response to chronic liver injury which is associated with excessive accumulation of extracellular matrix (ECM) proteins. Hepatic stellate cells (HSCs) are the main ECM-producing cells during liver fibrosis and have been considered to play a key role in this context. Owing to their potent chemotactic and immunoregulatory properties, chemokines contribute to the development of liver fibrosis. Macrophage migration inhibitory factor (MIF) is a pleiotropic inflammatory cytokine, which has recently been recognized to function as a chemokine-like function (CLF) cytokine in chronic inflammatory diseases. A contribution of MIF to liver fibrosis has been has not yet been systematically investigated. To address this question, we compared mif-/- with wild-type mice in the CCl4-induced fibrosis model. Remarkably, histological (Sirius red staining) analysis as well as hepatic hydroxyproline content (P <0.01), collagen expression and the expression of tissue inhibitors of metalloproteinases (TIMPs) and TGF-β1 (all P <0.01) revealed a considerably stronger fibrotic response in the mif-/- mice compared to wild-type mice. These data were confirmed in an independent model, i.e. when inducing liver fibrosis with thioacetamide (TAA) for six weeks. Given the well-established pro-inflammatory spectrum of MIF activity in various diseases, this unexpectedly, yet clearly, suggested a protective role of MIF during the progression of liver fibrosis in these two models. To unravel the underlying molecular mechanisms we have already detected the functional MIF receptors CD74, CXCR2 and CXCR4 on hepatic stellate cells and currently investigate the relevant intracellular signalling pathways in several hepatic cell types mediating the protective effect of MIF in toxically induced liver fibrosis.

Background and Aims: Concanavalin A (ConA)-induced hepatotoxicity may serve as a model for T cell-mediated fulminant hepatitis and liver failure.It has been shown that interleukin-18 (IL-18) is a central mediator of ConA-induced liver injury; indeed, inhibition of IL-18 in IL-18binding protein-transgenic mice could abrogate ConA-induced hepatotoxicity.However, it is not clear how IL-18 may mediate hepatotoxicity.Methods: To explore the role of lL-18 in hepatotoxicity, we generated IL-18-transgenic mice, which over-express active IL-18 under control of the hepatocyte-specific albumin-promoter.ConA (20 mg/kg) was administered intraveneously to IL-18-transgenic or non-transgenic mice and, after 8 hours, liver injury was assessed by measuring alanine-aminotransferase (ALT) levels in serum.Liver histology was assessed to confirm hepatotoxicity.In addition, the serum levels of interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, and IL-10 were measured at 2 or 8 hours after ConA-administration; cytokine production was confirmed by real-time RT-PCR.Results: IL-18-transgenic mice did not display any spontaneous liver pathology, although manifesting strongly elevated serum levels of IL-18 (25 ng/ml).However, after ConA administration, IL-18-transgenic mice expressed significantly higher levels of IFN-gamma than non-transgenic mice (30280±13970 vs. 8806±3710 fold induction; p < 0.0001) and TNFalpha (1130±247 vs. 279±68 fold induction; p < 0.05); in contrast, the levels of IL-10 were significantly reduced in the IL-18-transgenic mice (0.015±0.008 vs. 2.853±1.9fold induction; p < 0.0001).Liver injury was significantly higher in IL-18-transgenic mice, as assessed by histology and by serum ALT (363.5±73.17 vs. 143±26 U/l; p < 0.0001).Conclusions: Our findings indicate that elevated IL-18 alone is not sufficient to cause liver injury; however, IL-18 seems to increase ConAinduced inflammatory cytokine secretion and hepatotoxicity.Thus, the detrimental activity of IL-18 seems to depend on its role of an amplifier of the inflammatory cytokine response to ConA.

Administration of the isoflavone genistein (GEN) has been described to result in bone protection but also to induce uterotrophic responses. To compare bone protective effects of GEN with an isoflavone-rich diet (IRD) and to further elucidate molecular mechanisms involved in bone-protection, ovariectomized rats (OVX) received either a diet low in isoflavone content (IDD) enriched with GEN (42 mg kg(-1)b.wtd(-1)) (GEN(d)), an IRD (14 mg kg(-1)b.wtd(-1) GEN, 14 mg kg(-1)b.wtd(-1) daidzein) or were treated subcutaneously (s.c.) with GEN (10 mg kg(-1)b.wtd(-1)) (GEN(sc)) for 12 weeks. Intact (SHAM), vehicle treated OVX animals and those substituted with 17beta-estradiol (2microg kg(-1)b.wtd(-1)) (E(2)), served as controls. OVX-induced bone loss could be antagonized in E(2), GEN(sc), GEN(d) and IRD groups. Uterine wet weight (UWW) was only stimulated in E(2) and GEN(sc) animals. Serum biomarkers of bone-formation (osteocalcin, osteopontin) and bone-resorption (telopeptides of collagen type I, pyridinoline cross-links) were elevated in OVX compared to SHAM and E(2) animals. Feeding IRD stimulated bone-formation and inhibited bone-resorption, whereas s.c. or dietary administration of GEN only resulted in a stimulation of bone-formation. The results of the present study indicate that in contrast to s.c. administration, dietary intake of GEN resulted in bone protection without stimulation of UWW. Dietary intake of isoflavones by an IRD also did not result in a stimulation of UWW, yet IRD appeared to be more effective in bone protection than administration of pure GEN.

Aims: Chemokines are important mediators during liver injury through modulation of immune cell recruitment. The CXCR3 ligand CXCL9 is the main chemokine for NK and NKT cell recruitment to the liver, but the role of CXCR3/CXCL9 during acute liver injury is not established. It was the aim of the current study to investigate the role of the CXCR3/CXCL9 axis during acute liver injury.