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• W2152670054 abstract "A majority of typical pathologic sequelae of rickettsial diseases, such as altered barrier function of endothelial cells leading to compromised vascular permeability, manifest as non-cardiogenic pulmonary oedema/acute respiratory distress syndrome and parenchymal cerebral oedema, which can be attributed to disseminated infection and damage of the vascular endothelium [1Walker DH Rickettsiae and rickettsial infections: the current state of knowledge.Clin Infect Dis. 2007; 45: S39-S44Crossref PubMed Scopus (146) Google Scholar]. Endothelial cells infected in vitro with R. rickettsii or R. conorii undergo profound phenotypic modifications to an ‘activated’ state due to induction of a number of immediate early responsive prothrombotic and proadhesive genes [2Sahni SK Endothelial cell infection and hemostasis.Thromb Res. 2007; 119: 531-549Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar]. Ample published evidence also indicates an important role for interferons (IFNs) in host response and clearance of pathogenic Rickettsia species [3de Sousa R Ismail N Nobrega SD et al.Intralesional expression of mRNA of interferon-γ, tumor necrosis factor-α, interleukin-10, nitric oxide synthase, indoleamine-2, 3-dioxygenase, and RANTES is a major immune effector in Mediterranean spotted fever rickettsiosis.J Infect Dis. 2007; 196: 770-781Crossref PubMed Scopus (41) Google Scholar]. In general, both type I (α, β) and type II (c) IFNs modulate the innate immune response through Janus kinase (JAK)-STAT (Signal transducer and activator of transcription) mediated gene regulation. JAK-STAT pathway transmits signals originating from extracellular ligands and those from within the cell directly to the nucleus to control various gene promoters. There are four known Janus kinases (JAK -3 and TYK2) and seven STAT proteins (STAT1-4, 5a, 5b, and 6). To better understand the immune response of vascular endothelium to infection with spotted fever rickettsiae, we have initiated efforts to investigate the contributions of the JAK-STAT signalling pathway to the pathophysiology of human spotted fever group (SFG) rickettsioses. Standard laboratory protocols established and described earlier were used for in vitro infection of cultured human umbilical vein-derived endothelial cells (HUVECs) [4Sahni SK Van Antwerp D Silverman DJ et al.Proteasome-independent activation of nuclear factor-κβ in cytoplasmic extracts from human endothelial cells by Rickettsia rickettsii.Infect Immun. 1998; 66: 1827-1833PubMed Google Scholar]. Briefly, cells were incubated in antibiotic-free culture medium with approximately 6 × 104 pfu of R. rickettsii organisms for every cm2 of culture area. Indirect immunofluorescent staining and citrate synthase (gltA)-based quantitative PCR confirmed that this experimental protocol consistently resulted in infection of ≥80% of cells with three to five rickettsiae at 6 h [5Rydkina E Sahni A Silverman DJ Sahni SK Comparative analysis of host-cell signalling mechanisms activated in response to infection with Rickettsia conorii and Rickettsia typhi.J Med Microbiol. 2007; 56: 896-906Crossref PubMed Scopus (20) Google Scholar]. Because phosphorylation of specific target residues triggers subsequent dimerisation and nuclear translocation, activation of different STAT proteins was determined by denaturing polyacrylamide gel electrophoresis of total protein lysates from R. rickettsii-infected HUVECs followed by Western blot analysis using phosphorylation state-specific antibodies. As expected, uninfected endothelial cells were found to have either very low or negligible basal phosphorylation levels of all investigated STAT proteins. In response to R. rickettsii infection, however, the phosphorylation of STAT3 and STAT1 was clearly induced (Fig. 1), while that of STAT2, STAT5 and STAT6 remained unaltered at all times (not shown). Interestingly, there were noticeable differences in the kinetics of activation of STAT1 and STAT3 in response to infection. The levels of p-STAT3 in infected cells were two to three times higher than corresponding controls at early times of 1.5 and 3 h and then declined to basal levels at 8 h post-infection (Fig. 1a). In contrast, the levels of p-STAT1 did not display significant changes early during the infection and started to increase at about 6 h post-infection with as much as four-fold and eight-fold induction at 12 h and 24 h post-infection, respectively (Fig. 1b). These results indicate that activation of only selective STAT proteins occurs in response to R. rickettsii infection and highlight the unique differences in kinetics of their activation. Because phosphorylated STAT proteins act as transcription factors, which can therefore translocate to the nucleus and bind to DNA, electrophoretic mobility shift assays (EMSA) were next carried out to investigate DNA-protein interactions. The nuclear protein extracts were prepared from cells infected with R. rickettsii for varying lengths of time and corresponding uninfected controls according to established procedures with appropriate modifications [4Sahni SK Van Antwerp D Silverman DJ et al.Proteasome-independent activation of nuclear factor-κβ in cytoplasmic extracts from human endothelial cells by Rickettsia rickettsii.Infect Immun. 1998; 66: 1827-1833PubMed Google Scholar]. The double-stranded consensus nucleotide probes containing specific binding motifs for STAT3 and STAT1, respectively, were used: 5′-GATCCTTCTGGGAATTCCTAGATC-3’ and 5′-CATGTTATGCATATTCCTGTAAGTG-3′. The end-labelling of nucleotide probes, DNA–protein binding reactions, separation of DNA–protein complexes on native polyacrylamide gels, and visualisation of shifted bands, were performed as previously described [4Sahni SK Van Antwerp D Silverman DJ et al.Proteasome-independent activation of nuclear factor-κβ in cytoplasmic extracts from human endothelial cells by Rickettsia rickettsii.Infect Immun. 1998; 66: 1827-1833PubMed Google Scholar]. To confirm the specificity of DNA binding activity, an excess of unlabelled DNA probe was added to the mixture of labelled probe and nuclear extract. Again, there was either very minimal or no constitutive STAT3 and STAT1 DNA binding in uninfected endothelial cells. Infection with R. rickettsii resulted in rapid activation of STAT3 DNA-binding with a peak activity at 7 h followed by return to the baseline at later times of 14 and 21 h post-infection. In agreement with the evidence for delayed phosphorylation, nuclear translocation and DNA binding of STAT1 were significantly enhanced over basal activity at 14 and 21 h after infection with R. rickettsii, whereas no changes were evident at early times of 3 and 7 h (data not shown). Taken together, these findings indicate that although both STAT1 and STAT3 are activated in response to endothelial cell infection with R. rickettsii, there also exist significant differences in the patterns (kinetics as well as intensity) of their activation. This work was supported in part by research grant AI 040689 from the National Institutes of Health." @default.
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• W2152670054 date "2009-12-01" @default.
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• W2152670054 title "Selective activation of signal transducer and activator of transcription (STAT) proteins STAT1 and STAT3 in human endothelial cells infected with Rickettsia rickettsii" @default.
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• W2152670054 doi "https://doi.org/10.1111/j.1469-0691.2008.02248.x" @default.
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