The outcome of sepsis and septic shock has not significantly improved in recent decades despite the development of numerous drugs and supportive care therapies. To reduce sepsis-related mortality, a better understanding of molecular mechanism(s) associated with the development of sepsis and sepsis-related organ injury is essential. There is increasing evidence that Toll-like receptors (TLRs) play a key role in the mediation of systemic responses to invading pathogens during sepsis. However, the role of TLRs in the development of sepsis and in sepsis-related organ injury remains debatable. In this review, we focus on the biological significance of TLRs during sepsis. Medline was searched for pertinent publications relating to TLRs, with emphasis on their clinical and pathophysiological importance in sepsis. In addition, a summary of the authors' own experimental data from this field was set in the context of current knowledge regarding TLRs. In both animal models and human sepsis, TLRs are highly expressed on monocytes/macrophages, and this TLR expression may not simply be a ligand-specific response in such an environment. The fact that TLR signaling enables TLRs to recognize harmful mediators induced by invading pathogens may be associated with a positive feedback loop for the inflammatory response among different cell populations. This mechanism(s) may contribute to the organ dysfunction and mortality that occurs in sepsis. A better understanding of TLR biology may unveil novel therapeutic approaches for sepsis.

CD47 is an antiphagocytic molecule that acts via ligation to signal regulatory protein alpha on phagocytes; its enhanced expression and therapeutic targeting have recently been reported for several malignancies. However, CD47 expression in gastric cancer is not well documented. Immunohistochemical expression of CD47 in surgical specimens was investigated. Expression of CD47 and CD44, a known gastric cancer stem cell marker, were investigated in gastric cancer cell lines by flow cytometry. MKN45 and MKN74 gastric cancer cells were sorted by fluorescence‐activated cell sorting according to CD44 and CD47 expression levels, and their in vitro proliferation, spheroid‐forming capacity, and in vivo tumorigenicity were studied. In vitro phagocytosis of cancer cells by human macrophages in the presence of a CD47 blocking monoclonal antibody (B6H12) and the survival of immunodeficient mice intraperitoneally engrafted with MKN45 cells and B6H12 were compared to experiments using control antibodies. Immunohistochemistry of the clinical specimens indicated that CD47 was positive in 57 out of 115 cases, and its positivity was an independent adverse prognostic factor. Approximately 90% of the MKN45 and MKN74 cells expressed CD47 and CD44. CD47^hi gastric cancer cells showed significantly higher proliferation and spheroid colony formation than CD47^lo, and CD44^hiCD47^hi cells showed the highest proliferation in vitro and tumorigenicity in vivo. B6H12 significantly enhanced in vitro phagocytosis of cancer cells by human macrophages and prolonged the survival of intraperitoneal cancer dissemination in mice compared to control antibodies. In conclusion, CD47 is an adverse prognostic factor and promising therapeutic target in gastric cancer.

Helicobacter pylori infection is a leading cause of gastric cancer, which is the second-most common cancer-related death in the world. The chronic inflammatory environment in the gastric mucosal epithelia during H. pylori infection stimulates intracellular signaling pathways, namely inflammatory signals, which may lead to the promotion and progression of cancer cells. We herein report two important signal transduction pathways, the LPS-TLR4 and CagA-MET pathways. Upon H. pylori stimulation, lipopolysaccharide (LPS) binds to toll-like receptor 4 (TLR4) mainly on macrophages and gastric epithelial cells. This induces an inflammatory response in the gastric epithelia to upregulate transcription factors, such as NF-κB, AP-1, and IRFs, all of which contribute to the initiation and progression of gastric cancer cells. Compared with other bacterial LPSs, H. pylori LPS has a unique function of inhibiting the mononuclear cell (MNC)-based production of IL-12 and IFN-γ. While this mechanism reduces the degree of inflammatory reaction of immune cells, it also promotes the survival of gastric cancer cells. The HGF/SF-MET signaling plays a major role in promoting cellular proliferation, motility, migration, survival, and angiogenesis, all of which are essential factors for cancer progression. H. pylori infection may facilitate MET downstream signaling in gastric cancer cells through its CagA protein via phosphorylation-dependent and/or phosphorylation-independent pathways. Other signaling pathways involved in H. pylori infection include EGFR, FAK, and Wnt/β-Catenin. These pathways function in the inflammatory process of gastric epithelial mucosa, as well as the progression of gastric cancer cells. Thus, H. pylori infection-mediated chronic inflammation plays an important role in the development and progression of gastric cancer.