Repressed TGF-β signaling through CagA-Smad3 interaction aspathogenic mechanisms of Helicobacter pylori-associatedgastritis

摘要

Helicobacter pylori (H. pylori) infection causes chronic gastric inflammation, peptic ulceration, and gastric carcinogenesis, in which H. pylori cytotoxin-associated gene A (CagA) plays major pathogenic action. Since transforming growth factor-β (TGF-β) and its signaling also are principally implicated in either modulating gastric mucosal inflammatory responses or causing carcinogenesis and are attenuated after H. pylori infection, we hypothesized that dysregulated Smad signaling and repressed TGF-β might be core pathogenic mechanism for H. pylori-associated gastritis or carcinogenesis. Until now, no precise underlying mechanism how deranged TGF-β signaling developed after H. pylori infection relevant to various clinical manifestations remains unclear. In this study, we examined the molecular mechanism about the inhibition of TGF-β signaling by H. pylori CagA protein. H. pylori CagA significantly suppressed TGF-β/Smad transcriptional responses through critical inhibition of Smad3, though CagA interacted constitutively with Smad2, Smad3, and Smad4. CagA inhibited TGF-β-induced suppression of proinflammatorychemokines, such as IL-8, CXCL1 and CXCL3, as well as TGF-β-inducedtranscription of target genes. In conclusion, repressed TGF-β signalingassociated with CagA-positive H. pylori infection could be animportant determinant for the outcome of H. pylori infection.Therefore, TGF-β signaling is one of the important determinants to avoidfrom H. pylori CagA pathogenicity.