Gallotannin Inhibits the Expression of Chemokines and Inflammatory Cytokines in A549 Cells

Abstract

Tannins are plant-derived water-soluble polyphenols with wideranging biological activities. The mechanisms underlying the anti-inflammatory effect of tannins are not fully understood and may be the result of inhibition of poly(ADP-ribose) (PAR) glycohydrolase (PARG), the main catabolic enzyme of PAR metabolism. Therefore, we set out to investigate the mechanism of the anti-inflammatory effect of gallotannin (GT) in A549 cells with special regard to the role of poly(ADP-ribosyl)ation. Using an inflammation-focused low-density array and reverse transcription-polymerase chain reaction, we found that GT suppressed the expression of most cytokines and chemokines in cytokine-stimulated A549 cells, whereas the PARP inhibitor PJ-34 only inhibited few transcripts. Activation of the transcription factors, nuclear factor B (NF-B) and activator protein 1 (AP-1), was blocked by GT, whereas PJ-34 only suppressed NF-B activation but not AP-1 activation. GT also inhibited IB phosphorylation and nuclear translocation of NF-B, but PJ-34 had no effect on these upstream events. In the AP-1 pathway, GT treatment, even in the absence of cytokines, caused maximal phosphorylation of c-Jun N-terminal kinase and c-Jun. GT also caused a low-level phosphorylation of p38, extracellular signal-regulated kinases 1 and 2, activating transcription factor2, and cAMP-response element-binding protein but inhibited cytokine-induced phosphorylation of these kinases and transcription factors. GT inhibited protein phosphatases 1 and 2A, which may explain the increased phosphorylation of mitogenactivated protein kinase and their substrates. GT exerted potent antioxidant effect but failed to cause PAR accumulation. In summary, the potent inhibitory effects of GT on the transcription of cytokine and chemokine genes are probably not related to PARG inhibition. Inhibition of AP-1 activation and upstream signaling events may be responsible for the effects of GT.Tannins are water-soluble polyphenols that are widely distributed in the plant kingdom, including food grains and fruits. So far, more than a thousand different tannins have been characterized and ordered into four major groups: 1) gallotannins (GT), 2) ellagitannins, 3) complex, and 4) condensed tannins, with gallotannins and ellagitannins considered the most widespread types. The common structural elements of all tannins include one or more polyol units (mostly D-glucose) and one or more polyphenols (gallic acid, 3,4,5-trihydroxyl benzoic acid).The simplest hydrolyzable tannin, gallotannin, is a mixture of polygalloyl esthers of glucose. Gallotannin and other tannins have been shown to exert various biological effects ranging from anti-inflammatory to anticancer and antiviral effects (Fong et al., 1972;Mota et al., 1985;Uchiumi et al., 1996;Van Molle et al., 2000;Feldman et al., 2001). The mechanisms underlying the anti-inflammatory effect of tannins include the scavenging of radicals (antioxidant effect) (Hagerman et al., 1999) and inhibition of the expression of

Gallotannin inhibits NFĸB signaling and growth of human colon cancer xenografts

“…Day zero on the graph is day 7 after tumor injection. *Denotes significant differences (p < 0.05) with respect to control (days [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19], † significant with respect to prevention group at day 14. (B) Real time pCR analysis of TNFα, IL-1α and IL6 in the tumor tissue sections of control and GT-treated mice.…”

“…17 In the nucleus, NFκB binds DNA thus enhancing the transcription of various gene products that regulate proliferation, apoptosis, angiogenesis, invasion, inflammation and metastasis. 18 Since GT was found to inhibit NFκB mediated transcription in lung epithelial cells, 19 we postulated that the anti-colon cancer properties of GT may be through the regulation of the NFκB pathway. GT effects on NFκB activation and regulated gene expression was studied in the two human colon cancer cell lines, HCT-116 (p53 +/+ ) and HT-29 (p53 +/-).…”

Effect of silencing PARG in human colon carcinoma LoVo cells on the ability of HUVEC migration and proliferation

“…Many studies 41 have shown that NF-kB have a very important role in invasion and metastasis of colon carcinoma through Group iMVD upregulating of MMP-2, MMP-9 expressions. Beside, it was found that inhibiting PARP could also downregulate NF-kB activity, and further downregulate NF-kB-dependent gene expressions.…”

Poly(ADP-ribose) Polymerase-1 Inhibition in Brain Endothelium Protects the Blood—Brain Barrier under Physiologic and Neuroinflammatory Conditions

“…Anti-inflammatory effects of PARP have been documented in several in vivo and in vitro studies; 33,34,36 however, data on PARP inhibition in endothelial cells are just emerging. We selectively inhibited PARP in brain endothelium and showed that monocyte adhesion to TNFα-stimulated BMVEC and migration across BMVEC monolayers were attenuated by PARP inhibition (Figure 3).…”