Helicobacter pyloriCagA-Dependent Macrophage Migration Inhibitory Factor Produced by Gastric Epithelial Cells Binds to CD74 and Stimulates Procarcinogenic Events

Abstract

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that has recently been implicated in carcinogenesis. Helicobacter pylori, which is closely linked to gastric cancer, induces the gastric epithelium to produce proinflammatory cytokines, including MIF. MIF can bind to CD74, which we have previously shown to be highly expressed on the surface of gastric epithelial cells (GEC) during H. pylori infection. In this study, we sought to investigate the role of the H. pylori-induced MIF on epithelial proliferation and procarcinogenic events. Upon establishing a role for the H. pylori CagA virulence factor in MIF production, MIF binding to CD74 on GEC was confirmed. rMIF and H. pylori were shown to increase GEC proliferation, which was decreased when cagA− strains were used and when CD74 was blocked by mAbs. Apoptosis was also decreased by MIF, but increased by cagA− strains that induced much lower amounts of MIF than the wild-type bacteria. Furthermore, MIF binding to CD74 was also shown to decrease p53 phosphorylation and up-regulate Bcl-2 expression. This data describes a novel system in which an H. pylori virulence factor contributes to the production of a host factor that in turn up-regulates procarcinogenic events by the gastric epithelium.

MicroRNA dysregulation in gastric cancer: a new player enters the game

“…Serum levels of MIF are also elevated in gastric cancer patients (He et al, 2006). It has been demonstrated that MIF binds to CD74 to reduce apoptosis in gastric epithelial cells through downregulation of p53 phosphorylation and upregulation of Bcl-2 expression (Beswick et al, 2006). MIF also promotes gastric epithelial cell proliferation through transactivation of epidermal growth factor receptor (Beswick and Reyes, 2008) and the PI3K/Akt pathway .…”

Expression of CD74, the Receptor for Macrophage Migration Inhibitory Factor, in Non-Small Cell Lung Cancer

“…11,24,41-43 CD74-dependent signaling of extracellular MIF has been identified in gastric, 41 prostate, 42 and breast 24 carcinoma cells in vitro. A study done by Ioachim and colleagues 29 intended to examine the reactivity of a panel of lymphoid monoclonal antibodies against 25 lung cancer specimens, in which the LN2 monoclonal antibody (against CD74) was one of the antibodies which demonstrated reactivity with NSCLC (but not small cell, SCLC).…”

Macrophage Migration Inhibitory Factor and Interleukin-8 Produced by Gastric Epithelial Cells during Helicobacter pylori Exposure Induce Expression and Activation of the Epidermal Growth Factor Receptor

“…Thereby, CagA is the virulence factor most often associated with procarcinogenic host responses. We have previously shown that CagA is responsible for the induction of gastric epithelial cell production of MIF (5). MIF has been shown to mediate both inflammatory and proliferative responses in many cell types by inducing the NF-B, Erk1/2, and AP-1 signaling pathways (16,26,36).…”

“…The signals triggered by H. pylori binding to the epithelium lead to various responses, including the production of proinflammatory cytokines and altered cell turnover rates (5). A major virulence factor of H. pylori, the cytotoxin-associated pathogenicity island (cag PAI) has been shown to be responsible for many signaling pathways associated with the epithelial release of cytokines and chemokines, such as interleukin-8 (IL-8) (9,22) and macrophage migration inhibitory factor (MIF) (5).…”

“…A major virulence factor of H. pylori, the cytotoxin-associated pathogenicity island (cag PAI) has been shown to be responsible for many signaling pathways associated with the epithelial release of cytokines and chemokines, such as interleukin-8 (IL-8) (9,22) and macrophage migration inhibitory factor (MIF) (5). Upon H. pylori attachment to an epithelial cell, the cag PAI, which encodes a type IV secretion system, injects the CagA protein into the cells along with muropeptides that may elicit cell responses (11).…”