SUMMARYToll-like receptors (TLRs) expressed by mucosal epithelium play an essential role in the defense against microbes by recognizing conserved bacterial molecules. For the first time TLR4, TLR5 and TLR9 have been microanatomically localized in patients with noninflamed gastric mucosa and Helicobacter pylori gastritis by immunohistochemistry. Because polarized expression of TLRs in apical and basolateral epithelial compartments is thought to modulate mucosal immunity, subcellular TLR distribution by gastric epithelium was investigated using confocal microscopy. TLR4, TLR5 and TLR9 were expressed by gastric epithelium in antrum and corpus of all patients with H. pylori gastritis ( n = 14) and with noninflamed gastric mucosa ( n = 5). TLR4 was expressed at the apical and the basolateral pole of the gastric epithelium as well in noninflamed gastric mucosa as in H. pylori gastritis. TLR5 and TLR9 expression in the noninflamed gastric mucosa was identical to that of TLR4 with localization at the apical and the basolateral epithelial pole. However, in H. pylori gastritis TLR5 and TLR9 expression on the gastric epithelium changed to an exclusive basolateral localization without detectable expression at the apical pole. In the human stomach, the gastric epithelium expressed TLR4, TLR5 and TLR9, which gives it the possibility to interact with H. pylori . Furthermore, gastric epithelial TLR4 expression is highly polarized in an apical and a basolateral compartment, whereas TLR5 and TLR9 polarization seems to be a process dynamically influenced by H. pylori infection. This polarized and dynamically regulated gastric epithelial expression of TLRs supports a sentinel role for these receptors in the mucosal immunity to H. pylori .

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SummaryGuinea pigs are highly susceptible to Legionella pneumophila infection and therefore have been the preferred animal model for studies of legionellosis. In this study guinea pig infections revealed that the Legionella virulence factor Mip (macrophage infectivity potentiator) contributes to the bacterial dissemination within the lung tissue and the spread of Legionella to the spleen. Histopathology of infected animals, binding assays with components of the extracellular matrix (ECM), bacterial transmigration experiments across an artificial lung epithelium barrier, inhibitor studies and ECM degradation assays were used to elucidate the underlying mechanism of the in vivo observation. The Mip protein, which belongs to the enzyme family of FK506-binding proteins (FKBP), was shown to bind to the ECM protein collagen (type I, II, III, IV, V, VI). Transwell assays with L. pneumophila and recombinant Escherichia coli HB101 strains revealed that Mip enables these bacteria to transmigrate across a barrier of NCI-H292 lung epithelial cells and ECM (NCI-H292/ECM barrier). Mipspecific monoclonal antibodies and the immunosuppressants rapamycin and FK506, which inhibit the peptidyl prolyl cis/trans isomerase (PPIase) activity of Mip, were able to inhibit this transmigration. By using protease inhibitors we found that the penetration of the NCI-H292/ECM barrier additionally requires a serine protease activity. Degradation assays with 35 Slabelled ECM proteins supported the finding of a concerted action of Mip and a serine protease. The described synergism between the activity of the collagen binding Mip protein and the serine protease activity represents an entirely new mechanism for bacterial penetration of the lung epithelial barrier and has implications for other prokaryotic and eukaryotic pathogens.

SUMMARYCXC chemokines modulate host immunity, neovascularization, growth and invasive behaviour of tumours. Despite their relevance in tumour biology, chemokine expression in intestinal-and diffusetype gastric carcinoma, which exhibit a completely different growth pattern, has not been investigated in detail. In this study, expression of the CXC chemokines CXCL8 [interleukin (IL)-8], CXCL1 [growth-related oncogene alpha (Gro a )], CXCL9 [monokine induced by interferon (IFN)-g ] and CXCL10 [IFN-g -inducible protein-10 (IP-10)] and the corresponding chemokine receptors CXCR1-3 was investigated by immunohistochemistry in intestinal-and diffuse-type gastric carcinoma. Tumour cells of all patients expressed CXCL8. CXCL8 expression was significantly stronger in tumour cells of diffuse-rather than intestinal-type gastric carcinoma ( P < 0·01) as determined by a semiquantitative score. CXCL1 was expressed almost exclusively by diffuse-but not intestinal-type carcinoma cells. The corresponding chemokine receptors, CXCR1 and CXCR2, were found on carcinoma cells. Furthermore, CXCL8 expression correlated with number of tumour vessels ( P < 0·01), suggesting an angiogenetic function in gastric carcinoma not only in vitro but also in vivo . CXCL10 and CXCL9, attractants for T cells, were expressed by peritumorous macrophages in close proximity to IFN-g -producing CXCR3-positive T cells in both tumour types. These chemokines may attract gastric carcinomainfiltrating T cells via an IFN-g -mediated pathway and enhance host immunity against the tumour. In gastric carcinoma a complex interplay between CXC-chemokine signals derived from both tumour cells and tumour-infiltrating immune cells may exhibit pleiotropic effects in tumour biology that go far beyond their originally described functions as leucocyte chemoattractants. Because CXCL8 and CXCL1, which are known to increase growth and invasive behaviour of malignant tumours, are significantly stronger expressed in diffuse-than intestinal-type gastric carcinoma, one may speculate that these chemokines influence the different growth pattern of gastric carcinoma types.