Role of gap junctions and hemichannels in parasitic infections.

In vertebrates, connexins (Cxs) and pannexins (Panxs) are proteins that form gap junction channels and/or hemichannels located at cell-cell interfaces and cell surface, respectively. Similar channel types are formed by innexins in invertebrate cells. These channels serve as pathways for cellular communication that coordinate diverse physiologic processes. However, it is known that many acquired and inherited diseases deregulate Cx and/or Panx channels, condition that frequently worsens the pathological state of vertebrates. Recent evidences suggest that Cx and/or Panx hemichannels play a relevant role in bacterial and viral infections. Nonetheless, little is known about the role of Cx- and Panx-based channels in parasitic infections of vertebrates. In this review, available data on changes in Cx and gap junction channel changes induced by parasitic infections are summarized. Additionally, we describe recent findings that suggest possible roles of hemichannels in parasitic infections. Finally, the possibility of new therapeutic designs based on hemichannel blokers is presented.

Salmonella enhance chemosensitivity in tumor through connexin 43 upregulation.

The use of preferentially replicating bacteria as oncolytic agents is one of the innovative approaches for the treatment of cancer. The capability of Salmonella to disperse within tumors and hence to delay tumor growth was augmented when combined with chemotherapy. This work is warranted to elucidate the underlying mechanism of antitumor effects by the combination therapy of Salmonella and cisplatin. The presence of functional gap junctions is highly relevant for the success of chemotherapy. Following Salmonella treatment, dose- and time-dependent upregulation of connexin 43 (Cx43) expressions were observed. Moreover, Salmonella significantly enhanced gap intercellular communication (GJIC), as revealed by the fluorescent dye scrape loading assay. To study the pathway underlying these Salmonella-induced effects, we found that Salmonella induced a significant increase in mitogen-activated protein kinases (MAPK) signaling pathways. The Salmonella-induced upregulation of Cx43 was prevented by treatment of cells with the phosphorylated p38 inhibitor, but not phosphorylated extracellular signal-regulated kinase (pERK) inhibitor or phosphorylated c-jun N terminal kinase (pJNK) inhibitor. Specific knockdown of Cx43 had an inhibitory effect on GJIC and resulted in a reduction of cell death after Salmonella and cisplatin treatment. Our results suggest that accumulation of Salmonella in tumor sites leads to increase Cx43 gap junction communication and enhances the combination of Salmonella and cisplatin therapeutic effects.

Cell-cell propagation of NF-κB transcription factor and MAP kinase activation amplifies innate immunity against bacterial infection.

The enteroinvasive bacterium Shigella flexneri uses multiple secreted effector proteins to downregulate interleukin-8 (IL-8) expression in infected epithelial cells. Yet, massive IL-8 secretion is observed in Shigellosis. Here we report a host mechanism of cell-cell communication that circumvents the effector proteins and strongly amplifies IL-8 expression during bacterial infection. By monitoring proinflammatory signals at the single-cell level, we found that the activation of the transcription factor NF-κB and the MAP kinases JNK, ERK, and p38 rapidly propagated from infected to uninfected adjacent cells, leading to IL-8 production by uninfected bystander cells. Bystander IL-8 production was also observed during Listeria monocytogenes and Salmonella typhimurium infection. This response could be triggered by recognition of peptidoglycan and is mediated by gap junctions. Thus, we have identified a mechanism of cell-cell communication that amplifies innate immunity against bacterial infection by rapidly spreading proinflammatory signals via gap junctions to yet uninfected cells.

Diversity and properties of connexin gap junction channels.

Gap junction channels are composed of two apposing hemichannels (connexons) in the contiguous cells and provide a direct pathway for electrical and metabolic signaling between adjacent cells. The family of connexin genes comprises 20 members in the mouse and 21 genes in the human genome. Connexins are expressed in all tissues except differentiated skeletal muscle, erythrocytes, and mature sperm cells. Various tissues express more than one type of connexins; therefore, homotypic, heterotypic, and heteromeric gap junction channels may form between cells. In this article, we briefly review basic gating and permeability properties of homotypic and heterotypic gap junction channels as well as recent achievements in the research of their regulation by transjunctional voltage, intracellular calcium, pH, and phosphorylation.

Effects of H pylori infection on gap-junctional intercellular communication and proliferation of gastric epithelial cells in vitro.

AIM: To explore the effects of H pylori infection on gap-junctional intercellular communication (GJIC) and proliferation of gastric epithelial cells in vitro. METHODS: A human gastric epithelial cell line (SGC-7901) cultured on coverslips was exposed overnight to intact H pylori (CagA(+) or CagA(-) strains) and sonicated extracts, respectively. GJIC between the cells was detected by fluorescence redistribution after photobleaching (FRAP) technique. Proliferation of SGC cells was determined by methylthiazolyl tetrazolium (MTT) assay. RESULTS: When compared with control in which cells were cultured with simple medium alone, both CagA(+) and CagA(-) H pylori isolates could inhibit GJIC (CagA(+): F = 57.98, P < 0.01; CagA(-): F = 29.59, P < 0.01) and proliferation (CagA(+): F = 42.65, P < 0.01; CagA(-): F = 58.14, P < 0.01) of SGC-7901 cells. Compared with CagA(-) strains, CagA(+) H pylori more significantly down-regulated GJIC of gastric cells (intact H pylori: t = 13.86, P < 0.01; sonicated extracts: t = 11.87, P < 0.01) and inhibited proliferation gastric cells to a lesser extent in vitro (intact H pylori: t = 3.06, P < 0.05; sonicated extracts: t = 3.94, P < 0.01). CONCLUSION: Compared with CagA(-) H pylori strains, CagA(+) strains down-regulate GJIC of gastric epithelial cells more significantly and inhibit proliferation of gastric cells to a lesser extent in vitro. H pylori, especially CagA(+) strains, may play an important role in gastric carcinogenesis.