Gallotannin inhibits the expression of chemokines and inflammatory cytokines in A549 cells.
Tannins are plant-derived water-soluble polyphenols with wide-ranging 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 kappaB (NF-kappaB) and activator protein 1 (AP-1), was blocked by GT, whereas PJ-34 only suppressed NF-kappaB activation but not AP-1 activation. GT also inhibited IkappaB phosphorylation and nuclear translocation of NF-kappaB, 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 mitogen-activated 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.
Department of Medical Chemistry, Medical and Health Science Center, University of Debrecen, Elettudományi Epület 3.311, Egyetem tér 1, H-4032 Debrecen, Hungary.
Katalin
K
Erdèlyi
Andrea
A
Kiss
Edina
E
Bakondi
Péter
P
Bai
Csaba
C
Szabó
Pál
P
Gergely
Ferenc
F
Erdödi
László
L
Virag
D000975:Antioxidants / Q000494:pharmacology*; D001483:Base Sequence; D002460:Cell Line; D018925:Chemokines / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D017931:DNA Primers; D006801:Humans; D047348:Hydrolyzable Tannins / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010616:Phenanthrenes; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000819:agonists / Q000378:metabolism
D000975:Antioxidants; D018925:Chemokines; D016207:Cytokines; D017931:DNA Primers; D047348:Hydrolyzable Tannins; D018836:Inflammation Mediators; C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D010616:Phenanthrenes; D018808:Transcription Factor AP-1; D011064:Poly Adenosine Diphosphate Ribose