Einleitung: Adipozytokine spielen eine zentrale Rolle in der Pathophysiologie der nicht-alkoholischen Fettlebererkrankung. Auf der einen Seite gibt es Adiponectin, das vorwiegend anti-inflammatorische Eigenschaften besitzt. Auf der anderen Seite sollen Leptin, Resistin und „Pre-B cell enhancing factor (PBEF)/NAMPT/Visfatin vorwiegend als pro-inflammatorsiche Mediatoren fungieren, die sowohl metabolische als auch Immunfunktionen beeinflussen.

Hepatocyte growth factor (HGF) prevents liver failure in various animal models including endotoxin-induced acute liver failure. We were interested to find out whether human HGF exerts anti-inflammatory effects by modulation of cytokine synthesis. Therefore, human HepG2 cells were cultured with increasing concentrations of HGF. HGF dose-dependently upregulated the production of interleukin-1 receptor antagonist (IL-1Ra). Incubation of HepG2 cells with interleukin-1beta (IL-1beta) caused an increase in IL-1Ra levels, while interleukin-6 (IL-6) had no effect on IL-1Ra synthesis. Co-stimulation of HepG2 cells with HGF + IL-1beta resulted in a synergistic effect on IL-1Ra mRNA and protein expression. Stimulation of freshly isolated mouse hepatocytes from male C57 BL/6 mice with HGF increased IL-1Ra mRNA and protein synthesis dose-dependently. A co-stimulation with HGF and IL-1beta had a synergistic effect on IL-1Ra mRNA expression but only a partially additive effect on IL-1Ra protein synthesis. HGF-induced IL-1Ra production was significantly decreased by the mitogen-activated protein kinase (MAPK) inhibitor PD98059. Accordingly, HGF stimulation specifically increased MAPK-dependent signalling pathway (p42/44). In contrast, in preactivated PBMC mRNA expression and protein synthesis of IL-1Ra, interleukin-10 (IL-10) and tumor necrosis factor-alpha (TNF-alpha) were unaffected after stimulation with HGF. In conclusion, our data suggest that HGF exerts anti-inflammatory effects by modulating the signal transduction cascade leading to increased expression of IL-1Ra, which might explain the protective and regenerative properties of this cytokine in animal models of liver failure.

Baseline platelet production is dependent on thrombopoietin (TPO). TPO is constitutively produced and primarily regulated by receptor-mediated uptake by platelets. Inflammatory thrombocytosis is thought to be related to increased interleukin-6 (IL-6) levels. To address whether IL-6 might act through TPO to increase platelet counts, TPO was neutralized in vivo in C57BL/10 mice treated with IL-6, and hepatic TPO mRNA expression and TPO plasma levels were studied. Transcriptional regulation of TPO mRNA was studied in the hepatoblastoma cell line HepG2. Furthermore, TPO plasma levels were determined in IL-6-treated cancer patients. It is shown that IL-6-induced thrombocytosis in C57BL/10 mice is accompanied by enhanced hepatic TPO mRNA expression and elevated TPO plasma levels. Administration of IL-6 to cancer patients results in a corresponding increase in TPO plasma levels. IL-6 enhances TPO mRNA transcription in HepG2 cells. IL-6-induced thrombocytosis can be abrogated by neutralization of TPO, suggesting that IL-6 induces thrombocytosis through TPO. A novel pathway of TPO regulation by the inflammatory mediator IL-6 is proposed, indicating that the number of platelets by themselves might not be the sole determinant of circulating TPO levels and thus of thrombopoiesis. This regulatory pathway might be of relevance for the understanding of reactive thrombocytosis.

Hepatocyte growth factor (HGF), a cytokine involved in tissue regeneration, angiogenesis and lateral vessel growth, is secreted as a biological-inactive, single-chain precursor named pro-HGF. In case, of tissue injury pro-HGF is proteolytically cleaved at the extracellular locus by serine proteases. Results obtained from in vitro experiments showed that urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA) can cleave single-chain HGF. In this study we measured serum HGF levels in patients with acute myocardial infarction (MCI). Two groups of patients were compared. One group (n = 7) was treated with a conventional therapy and the other group (n = 7) was subjected to a thrombolytic therapy with recombinant tissue-type plasminogen activator (rtPA). Serum samples were collected at time of admission and subsequently 12-16 hours, 20-30 hours and 50-60 hours after onset of chest pain. At admission and before administration of rtPA, serum HGF levels peaked at 16.8 +/- 2.2 ng/ml in the lysed group and at 20.7 +/- 6.5 ng/ml in the non-lysed group. Levels then continuously declined, reaching lowest values 50-60 hours after onset of chest pain (3.2 +/- 1.3 ng/ml in the group treated with rtPA versus 4.4 +/- 0.9 ng/ml in the non-lysed group). No statistical significant difference could be detected between the two groups at any time. We suggest that serine proteases other than tPA are involved in HGF activation in vivo.

Interferon α (IFN-α) has proven its clinical usefulness in a variety of diseases of diverse pathogenesis. In addition to direct antiviral effects, recent evidence suggests that its interaction with the cytokine cascade might contribute to its mechanism of action. This study was undertaken to determine whether IFN-α influences the synthesis of interleukin 4 (IL-4) and IL-13, two cytokines which share many biological properties on various cells and tissues and which have a profound role in regulating immunological and inflammatory responses. Peripheral blood mononuclear cells (PBMC) from healthy volunteers were stimulated with Concanavalin A (ConA), phorbol myristate acetate (PMA), anti-CD3/CD28 mAbs, either alone or in various combinations, and incubated with increasing concentrations of IFN-α. IL-4 and IL-13 mRNA was determined by Northern hybridizations and IL-4 and IL-13 protein synthesis was evaluated by specific enzyme-linked immunosorbent assay (ELISA). IFN-α led to a profound decrease of IL-13 mRNA expression after an incubation period of 5 h with ConA alone or in combination with PMA, whereas it showed no regulatory effect on IL-4 mRNA expression. After an incubation period of 24 h, the decrease in IL-13 mRNA expression after addition of IFN-α was even more pronounced. At the protein level, IFN-α increased IL-4 synthesis dose dependently regardless of the mode of activation. This increase was most pronounced after stimulation with ConA or anti-CD28/PMA. In contrast, IL-13 synthesis was strongly downregulated by IFN-α in a dose-dependent manner irrespective of the activating agent. It is concluded that IL-4 and IL-13, although showing similar biological effects, are differentially regulated by IFN-α.