Neutrophils play an essential role in host defense and inflammation, but the latter may trigger and sustain the pathogenesis of a range of acute and chronic diseases. Green tea has been claimed to exert anti-inflammatory properties through unknown molecular mechanisms. We have previously shown that the most abundant catechin of green tea, (−)epigallocatechin-3-gallate (EGCG), strongly inhibits neutrophil elastase. Here we show that 1) micromolar EGCG represses reactive oxygen species activity and inhibits apoptosis of activated neutrophils, and 2) dramatically inhibits chemokine-induced neutrophil chemotaxis in vitro; 3) both oral EGCG and green tea extract block neutrophil-mediated angiogenesis in vivo in an inflammatory angiogenesis model, and 4) oral administration of green tea extract enhances resolution in a pulmonary inflammation model, significantly reducing consequent fibrosis. These results provide molecular and cellular insights into the claimed beneficial properties of green tea and indicate that EGCG is a potent anti-inflammatory compound with therapeutic potential.

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The anthrax lethal factor (LF) has a major role in the development of anthrax. LF is delivered by the protective antigen (PA) inside the cell, where it exerts its metalloprotease activity on the Nterminus of MAPK-kinases. PA þ LF are cytotoxic to macrophages in culture and kill the Fischer 344 rat when injected intravenously. We describe here the properties of some polyphenols contained in green tea as powerful inhibitors of LF metalloproteolytic activity, and how the main catechin of green tea, (À)epigallocatechin-3-gallate, prevents the LF-induced death of macrophages and Fischer 344 rats.

Green tea infusion has been shown to inhibit metastatic spreading of the transgenic adenocarcinoma of mouse prostate (TRAMP). Investigation on the molecular mechanisms triggered by the main green tea flavonoid, (؊)epigallocatechin-3-gallate (EGCG), shows that EGCG restrains TRAMP-C1 cell proliferation in a dose-dependent manner, at concentrations (IC 50 < 0.2 M) equivalent to those measured in the plasma of moderate green-tea drinkers. Up to 10 M, EGCG does not modify the cell-surface immuno-localization of MMP-2, one of the invasion-instrumental proteinases; but while in default culture conditions these cells secrete mainly pro-MMP-2, in the presence of reconstituted basement membrane (Matrigel) they release almost exclusively pro-MMP-9. In contrast, when stimulated to traverse Matrigel toward a chemo-attractant, in addition to pro-MMP-9, they secrete pro-MMP-2. In the presence of 0.2 M EGCG, only the level of the latter is markedly lowered in the conditioned medium, in parallel with the invasive behavior (>50%). In vivo, s.c. injection of TRAMP-C1 cells dispersed in Matrigel gives origin to a tumor mass, whose growth is not inhibited by green-tea regimen. This growth is contained greater than two-thirds by LPS-triggered polymorpho-nuclear phagocyte (PMN) recruitment but this effect is abolished by green tea. Nevertheless, while tumor-released pro-MMP-2 is activated by co-incubation of TRAMP-C1 cells with PMNs, in the presence of 10 M EGCG the activation is almost abolished. These results suggest that inflammatory involvement of prostate carcinoma could be efficaciously prevented by green tea with a concomitant lowering of the invasive potential. © 2004 Wiley-Liss, Inc. Key words: prostate carcinoma; TRAMP; neutrophils; MMP-2 activation; invasion; proliferation; EGCGProstate carcinoma (PCa) is the third most common cancer in men and the most common in Western society. 1 Although approximately 80% of early diagnosed and treated patients survive for Ͼ5 years, many of them face a fatal outcome due to progression to advanced metastatic stages. 2,3 Metastatic dissemination is a multi-step process in which the extracellular matrix (ECM) is degraded by proteolytic enzymes, in particular the matrix metalloproteinases MMP-2 and MMP-9, frequently overexpressed in cancer and angiogenesis. 4 Their proteolytic activity is regulated by membrane-bound activating proteases such as membrane type MMP (MT-MMP), 5 urokinase-type plasminogen activator (uPA) 6 and protease 3 (PR-3) 7 and by either specific tissue inhibitors of MMPs (TIMPs) or broad-spectrum inhibitors such as ␣2-macroglobulin and ␣1-protease inhibitor. 8 Several studies have provided evidence that MMP activity can induce or enhance tumor growth, invasion and metastasis in many types of cancer, including PCa where strong correlation was found between MMP-2 expression and tumor grading (Gleason score). 9 However, increased expression of MMP-2 and MMP-9 was also observed in benign prostatic hyperplasia, 10 and, in the case of prostate inflammation, additional proteases...

SUMMARY:Consumption of green tea has been associated with prevention of cancer development, metastasis, and angiogenesis. Given the crucial role of the matrix metallo-proteinase-2 (MMP-2) on the degradation of the extracellular matrix instrumental to invasion, we examined the effect of the main flavanol present, (-)epigallocatechin-3-gallate (EGCG), on membrane-type 1 MMP (MT1-MMP), the receptor/activator of MMP-2. In-solution fluorimetric assay with activated MT1-MMP and gelatin-zymography with MT1-MMP catalytic domain alone and pro-MMP-2 activation by the same domain revealed dose-dependent inhibition of MT1-MMP at EGCG concentrations slightly lower than that reported to inhibit MMP-2 and MMP-9. Cytofluorimetry and immunolocalization revealed that EGCG does not impair MT1-MMP/TIMP-2/MMP-2 presence on the cell membrane. In the membrane extract of HT-1080 human fibrosarcoma cells, 10 M EGCG caused a strong increase in MT1-MMP level and accumulation of pro-MMP-2 while leaving activated MMP-2 unchanged. EGCG thus exerts inhibition of MT1-MMP, which restrains activation of MMP-2; this may confer the antiangiogenic and antimetastatic activity associated with green tea. (Lab Invest 2002, 82:1685-1693.