Green tea has been reported to show anti-inflammatory properties because of its inhibitory effects on the expression of several pro-inflammatory genes. Because the inducible nitricoxide synthase (iNOS) plays an important role in chronic inflammatory diseases, we have focused our attention on the regulation of iNOS expression by green tea in two different human epithelial cell lines, alveolar A549/8 and colon DLD-1 cells. With the use of electrophoretic mobility shift assays, we found a green tea-mediated down-regulation of the DNA binding activity of the transcription factor signal transducer and activator of transcription-1␣ (STAT-1␣), but not of nuclear factor-B. This down-regulation of the STAT-1␣ DNA binding was shown to result from reduced tyrosine phosphorylation of the STAT-1␣ protein and not from antioxidative effects of the green tea extract. Green tea extract inhibited human iNOS expression in a concentration-dependent manner, quantified in terms of iNOS mRNA, iNOS protein, and nitric oxide production in both cell lines. This inhibitory effect of green tea resulted from transcriptional inhibition as shown in reporter gene experiments. These data suggest that green tea extracts may be promising at least as an auxiliary anti-inflammatory principle in chronic inflammatory diseases.

A great interest is emerging about green tea as a tool against human cancer development or inflammation, as pointed out by recent reports describing the inhibitory action of epigallocatechin gallate (EGCG), the main polyphenol component of green tea, on angiogenesis, urokinase, metalloproteinases, and induction of inducible nitric oxide synthase (NOS II). We proposed that EGCG may modulate a cell factor having wider spectra of action than those actions of single enzymes. Signal transducers and activators of transcription (STATs) are nuclear factors mediating the action of cytokines involved in various biological functions. Based on the knowledge that interferon (IFN)-γ-elicited STAT1 activation is important for NOS II expression and that STAT1 critically modulates proliferative and inflammatory processes, we hypothesized that STAT1 could be a target of EGCG. Here we show that 1) in human MDA-MB 231 cell line EGCG blocks IFN-γ-elicited activation of STAT1 by interfering with tyrosine phosphorylation; 2) EGCG suppresses the IFN-γ-elicited expression of NOS II as well as interferon regulating factor-1 (IRF-1); 3) EGCG inhibits IFN-γ-elicited STAT1 activation also in human HeLa, MCF7, MDA MB 468, and HepG2 cells; and 4) EGCG has no effect on interleukin (IL)-6-elicited STAT3 activation in IL6-responsive cells. These results indicate that EGCG could be used as a harmless drug to modulate STAT1 signaling in inflammatory processes and, in some cases, tumor formation.Key words: tumor • inflammation • green tea • tyrosine phosphorylation • inducible nitric oxide synthase • IRF-1 pidemiologic studies and experimental investigations have demonstrated that green tea has an inhibitory effect towards tumor formation and growth (1-4) and inflammation (5-7). Although the antioxidative property of catechins present in green tea such as EGCG and EGC is tentatively accounted for the reported inhibitory activity of green tea (1), the molecular basis of the action of catechins has for long time been elusive. Only recently some hints on the possible molecular mechanism of the antitumor or antiinflammatory effect of green tea have emerged. Epigallocatechin gallate (EGCG), the main polyphenol present in green tea E (8), inhibits urokinase (9), an enzyme indispensable for tumor invasion and metastasis, and angiogenesis (10), which is crucial for the growth of almost all types of tumor. In addition, EGCG efficiently suppresses the activity of matrix metalloproteinase-2 and -9, essential for tumor cells in cutting through basement membrane barriers (11), thus leading to an efficient inhibition of angiogenesis. EGCG also blocks the induction of the expression of NOS II in lipopolysaccharide (LPS)-activated mouse macrophages (12). NOS II, normally silent, is induced, not only in immune cells but also in many other human cell types by cytokines such as interferon γ (IFN-γ), tumor necrosis factor α (TNF-α), and interleukine1 β (IL1-β) in proinflammatory processes (13). Massive amounts of NO produced by NOS II may, on one side, be beneficial fo...

St. John's wort (SJW) has been described to show anti-inflammatory properties due to its inhibitory effects on the expression of pro-inflammatory genes like cyclooxygenase-2, interleukin-6, and inducible nitric-oxide synthase (iNOS). Since iNOS plays a critical role in chronic inflammatory diseases, we have focused our attention on the regulation of iNOS expression by SJW in two different human epithelial cell lines, alveolar A549/8 and colon DLD-1 cells. SJW extract concentration dependently inhibited human iNOS expression evaluated by measuring the amounts of iNOS mRNA, iNOS protein, and NO production in both cell lines. This inhibitory effect resulted from transcriptional inhibition as shown in reporter gene experiments. With electrophoretic mobility shift experiments, we found a SJWmediated down-regulation of the DNA binding activity of the transcription factor signal transducer and activator of transcription-1␣ (STAT-1␣), but not of nuclear factor-B. This downregulation of the STAT-1␣ DNA binding was shown to result from reduced tyrosine phosphorylation of the STAT-1␣ protein.The diminished STAT-1␣ tyrosine phosphorylation resulted from SJW-mediated reduction of Janus kinase 2 activity. These data suggest that extracts from SJW may be a promising anti-inflammatory principle in chronic inflammatory diseases.

No abstract

No abstract