interleukin-8 and 3-3--4-5--tetrahydroxystilbene

Liver fibrosis and fibrosis-associated hepatocarcinogenesis are driven by chronic inflammation and are leading causes of morbidity and death worldwide. SYK signaling regulates critical processes in innate and adaptive immunity, as well as parenchymal cells. We discovered high SYK expression in the parenchymal hepatocyte, hepatic stellate cell (HSC), and the inflammatory compartments in the fibrotic liver. We postulated that targeting SYK would mitigate hepatic fibrosis and oncogenic progression. We found that inhibition of SYK with the selective small molecule inhibitors Piceatannol and PRT062607 markedly protected against toxin-induced hepatic fibrosis, associated hepatocellular injury and intra-hepatic inflammation, and hepatocarcinogenesis. SYK inhibition resulted in increased intra-tumoral expression of the p16 and p53 but decreased expression of Bcl-xL and SMAD4. Further, hepatic expression of genes regulating angiogenesis, apoptosis, cell cycle regulation, and cellular senescence were affected by targeting SYK. We found that SYK inhibition mitigated both HSC trans-differentiation and acquisition of an inflammatory phenotype in T cells, B cells, and myeloid cells. However, in vivo experiments employing selective targeted deletion of SYK indicated that only SYK deletion in the myeloid compartment was sufficient to confer protection against fibrogenic progression. Targeting SYK promoted myeloid cell differentiation into hepato-protective TNFα

Topics: Animals; Carcinogenesis; Carcinoma, Hepatocellular; Cell Transdifferentiation; Cyclohexylamines; Female; Fibrosis; Hepatic Stellate Cells; Humans; Interleukin-8; Lectins, C-Type; Liver; Liver Cirrhosis; Liver Neoplasms; Male; Mannose Receptor; Mannose-Binding Lectins; Mice; Mice, Inbred C57BL; Myeloid Cells; Neoplasms, Experimental; Oxidative Phosphorylation; Phenotype; Pyrimidines; Receptors, Cell Surface; Signal Transduction; Stilbenes; Syk Kinase; Transcriptome

Inflammatory processes are involved in the etiology of diseases. We analyzed the effect of resveratrol, piceatannol, synthetic tri-acetoxystilbene (TAS), and genistein (Bonistein(TM)) on the production of inflammatory mediators including prostaglandin E2 (PGE2), tumor necrosis factor-alpha (TNF-alpha), interleukins, and chemokines, which participate in the progression of inflammation. In order to induce inflammatory responses, human peripheral blood mononuclear and/or polymorphonuclear leukocytes were stimulated with lipopolysaccharide (LPS) and interferon-gamma (IFN(gamma)) and the production of PGE2, interleukin-8 (IL-8), and TNF-alpha was determined. In response to the stimuli, genes were substantially activated within < 2 h (e. g., TNF-alpha, IL-1alpha), or at a later stage, (e. g., COX-2, IL-6, IL-8). Unlike genistein, resveratrol and related compounds dose-dependently reduced PGE2 production. Genistein, piceatannol, and TAS diminished secretion of TNF-alpha, and IL-8. TAS reduced mRNA levels of COX-2, TNF-alpha, IL-8, IL-6, and IL-1alpha, while resveratrol impaired early expression of IL-8 and TNF-alpha. Piceatannol out-performed resveratrol, yet without matching TAS. Genistein downregulated TNF-alpha and IL-8 expression. These substances altered the LPS/IFNgamma-induced gene expression in mononuclear cells rather than in polymorphonuclear leukocytes. Immunoblot analyses corroborated the distinct activity pattern of resveratrol and genistein. In conclusion, resveratrol and their derivatives attenuated the inflammatory response of PBLs at several levels, whereas genistein acts on cytokines and pro-inflammatory interleukins.

Topics: Cell Survival; Cyclooxygenase 2; Dinoprostone; Gene Expression; Genistein; Humans; Inflammation; Interferon-gamma; Interleukin-1; Interleukin-6; Interleukin-8; Leukocytes; Leukocytes, Mononuclear; Lipopolysaccharides; Membrane Proteins; Neutrophils; Prostaglandin-Endoperoxide Synthases; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Stilbenes; Tumor Necrosis Factor-alpha