Targeting hypoxia-inducible factor-1 alpha suppresses Helicobacter pylori-induced gastric injury via attenuation of both cag-mediated microbial virulence and proinflammatory host responses
Jennifer M. Noto,
M. Blanca Piazuelo,
Judith Romero-Gallo,
Alberto G. Delgado,
Giovanni Suarez,
Konstantina Akritidou,
Miguel Girod Hoffman,
Juan Carlos Roa,
Cormac T. Taylor,
Richard M. Peek
Affiliations
Jennifer M. Noto
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
M. Blanca Piazuelo
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
Judith Romero-Gallo
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
Alberto G. Delgado
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
Giovanni Suarez
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
Konstantina Akritidou
Department of Biology, Davidson College, Davidson, NC, USA
Miguel Girod Hoffman
School of Medicine, University of Puerto Rico, San Juan, USA
Juan Carlos Roa
Department of Pathology, School of Medicine, Center for Cancer Prevention and Control (CECAN), Pontificia Universidad Catolica de Chile, Santiago, Chile
Cormac T. Taylor
School of Medicine, Systems Biology Ireland and The Conway Institute, University College Dublin, Dublin, Ireland
Richard M. Peek
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
ABSTRACTHelicobacter pylori-induced inflammation is the strongest known risk factor for gastric adenocarcinoma. Hypoxia-inducible factor-1 (HIF-1α) is a key transcriptional regulator of immunity and carcinogenesis. To examine the role of this mediator within the context of H. pylori-induced injury, we first demonstrated that HIF-1α levels were significantly increased in parallel with the severity of gastric lesions in humans. In interventional studies targeting HIF-1α, H. pylori-infected mice were treated ± dimethyloxalylglycine (DMOG), a prolyl hydroxylase inhibitor that stabilizes HIF-1α. H. pylori significantly increased proinflammatory chemokines/cytokines and inflammation in vehicle-treated mice; however, this was significantly attenuated in DMOG-treated mice. DMOG treatment also significantly decreased function of the H. pylori type IV secretion system (T4SS) in vivo and significantly reduced T4SS-mediated NF-κB activation and IL-8 induction in vitro. These results suggest that prolyl hydroxylase inhibition protects against H. pylori-mediated pathologic responses, and is mediated, in part, via attenuation of H. pylori cag-mediated virulence and suppression of host proinflammatory responses.