IRAK-M Expression Limits Dendritic Cell Activation and Proinflammatory Cytokine Production in Response to Helicobacter pylori

Abstract

Helicobacter pylori (H. pylori) infects the gastric mucosa and persists for the life of the host. Bacterial persistence may be due to the induction of regulatory T cells (Tregs) whichmay have protective effects against other diseases such as asthma. It has been shown that H. pylori modulates the T cell response through dendritic cell reprogramming but the molecular pathways involved are relatively unknown. The goal of this study was to identify critical elements of dendritic cell (DC) activation and evaluate potential influence on immune activation. Microarray analysis was used to demonstrate limited gene expression changes in H. pylori stimulated bone marrow derived DCs (BMDCs) compared to the BMDCs stimulated with E. coli. IRAK-M, a negative regulator of TLR signaling, was upregulated and we selectedit for investigation of its role in modulating the DC and T cell responses. IRAK-M−/− and wild type BMDC were compared for their response to H. pylori. Cells lacking IRAK-M produced significantly greater amounts of proinflammatory MIP-2 and reduced amounts of immunomodulatory IL-10 than wild type BMDC. IRAK-M−/− cells also demonstrated increased MHC II expression upon activation. However, IRAK-M−/− BMDCs were comparable to wild type BMDCs in inducing T-helper 17 (TH17) and Treg responses as demonstrated in vitro using BMDC CD4+ T cells co-culture assays,and in vivo though the adoptive transfer of CD4+ FoxP3-GFP T cells into H. pylori infected IRAK-M−/− mice. These results suggest that H. pylori infection leads to the upregulation of anti-inflammatory molecules like IRAK-M and that IRAK-M has a direct impact on innate functions in DCs such as cytokine and costimulation molecule upregulation but may not affect T cell skewing.

<b><i>Helicobacter pylori</i></b> Inhibits Dendritic Cell Maturation via Interleukin-10-Mediated Activation of the Signal Transducer and Activator of Transcription 3 Pathway

“…In support of our findings, previous studies indicate that the DC sensing of bacterial products by Toll-like receptor 2 regulates IL-10 secretion [29]. Furthermore, Shiu et al [30 ]showed that Toll-like receptor 2 increased IRAK-M signaling, thereby contributing to IL-10 secretion during H. pylori infection. Alternatively, both γ-glutamyl transpeptidase and s2/m2 vacuolating cytotoxin secreted from H. pylori have been shown to contribute to the development of tolerizing DCs [31].…”

IRAK‐M regulates the inhibition of TLR‐mediated macrophage immune response during late in vitro Leishmania donovani infection

“…For example, IRAK‐M impaired host defense during pneumonia caused by Klebsiella pneumonia . Helicobacter pylori infection led to the upregulation of IRAK‐M, which was found to limit dendritic cell activation and proinflammatory cytokine production . Moreover, IRAK‐M overexpression promoted lung epithelial human rhino virus 16 (HRV‐16) replication and autophagy .…”

Immunity, Inflammation, and Vaccines for Helicobacter pylori

“…Shiu et al. aimed to identify which critical factor can influence DC activation and immune activation. Using microarray analysis IRAK‐M (−/−) bone marrow DCs, they demonstrated that IRAK‐M, a negative regulator of TLR signaling, is an important factor that limits dendritic cell activation and proinflammatory cytokine production in response to H. pylori .…”

“…Recent studies using the Helicobacter suis model have confirmed that c-glutamyl transpeptidase acts on lymphocytes and inhibits cell activation, proliferation, and cytokine production, whereas glutamine and glutathione supplementation restores T-cell function [26]. Shiu et al [27] aimed to identify which critical factor can influence DC activation and immune activation. Using microarray analysis IRAK-M (À/À) bone marrow DCs, they demonstrated that IRAK-M, a negative regulator of TLR signaling, is an important factor that limits dendritic cell activation and proinflammatory cytokine production in response to H. pylori.…”