Humans show variation in vulnerability to HIV-1 infection and especially in the clinical outcome after infection, a variability that is governed by multiple host genetic factors 1-3. Lens ...epithelium-derived growth factor (LEDGF/p75) is a lentivirus-specific cellular cofactor involved in the tethering of viral preintegration complex to cellular chromatin, directly interacting with viral integrase 4,5. The crucial role of LEDGF in HIV replication has been evidenced by mutagenesis, RNA interference, transdominant expression of protein domains and knockout studies 4-6. Small-molecule inhibitors of LEDGF-integrase interaction that block the integration step have been successfully developed, providing further evidence of the relevance of LEDGF as a HIV cellular cofactor 7. Recently, a series of single-nucleotide polymorphisms (SNPs) in LEDGF were associated to HIV-1 disease progression in two cohorts of African HIV-1-positive individuals 8. The SNP rs 12339417 was associated with slower decline of CD4 super(+) T cells and lower messenger RNA (mRNA) levels of LEDGF. The exonic SNP rs61744944 induced a missense mutation (Q472L) in the C-terminal region of the protein but without an apparent effect on HIV replication in cell culture.
TNF-related lymphotoxin alpha (LTalpha) is essential for the development of Plasmodium berghei ANKA (PbA)-induced experimental cerebral malaria (ECM). The pathway involved has been attributed to ...TNFR2. Here we show a second arm of LTalpha-signaling essential for ECM development through LTbeta-R, receptor of LTalpha1beta2 heterotrimer.
LTbetaR deficient mice did not develop the neurological signs seen in PbA induced ECM but died at three weeks with high parasitaemia and severe anemia like LTalphabeta deficient mice. Resistance of LTalphabeta or LTbetaR deficient mice correlated with unaltered cerebral microcirculation and absence of ischemia, as documented by magnetic resonance imaging and angiography, associated with lack of microvascular obstruction, while wild-type mice developed distinct microvascular pathology. Recruitment and activation of perforin(+) CD8(+) T cells, and their ICAM-1 expression were clearly attenuated in the brain of resistant mice. An essential contribution of LIGHT, another LTbetaR ligand, could be excluded, as LIGHT deficient mice rapidly succumbed to ECM.
LTbetaR expressed on radioresistant resident stromal, probably endothelial cells, rather than hematopoietic cells, are essential for the development of ECM, as assessed by hematopoietic reconstitution experiment. Therefore, the data suggest that both functional LTbetaR and TNFR2 signaling are required and non-redundant for the development of microvascular pathology resulting in fatal ECM.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The phenotypic and functional characteristics of microvascular endothelial cells derived from human liver cancer (HLCEC) were analyzed in vitro and compared with those of human liver sinusoidal ...endothelial cells (LSEC).
Flow-cytometric and real-time PCR analysis indicated that expressions of tumor necrosis factor receptor (TNFR) p75, alphavbeta3 and alphavbeta5 were increased, while those of TNFR p55 and intercellular-adhesion molecule 1 (ICAM-1) were decreased in HLCEC compared with LSEC. The functional analysis indicated that HLCEC exhibited higher angiogenic ability than LSEC, including proliferation capacity, ability to form capillary-like networks and release of matrix metalloproteinases. In response to tumor necrosis factor, LSEC exhibited a significant dose-dependent cytotoxicity, while HLCEC did not. Moreover, the coagulant and fibrinolytic capacity was increased in HLCEC. In addition, tumor cell adherence was significantly higher on HLCEC than on LSEC, while leukocyte adherence was lower on HLCEC than on LSEC. The cytoadherence of HLCEC was inhibited by antibodies against alphavbeta3 and alphavbeta5,and of LSEC by antibodies against ICAM-1.
These results indicate that tumor-derived endothelial cells are phenotypically and functionally different from those derived from normal liver tissue. These differences are valuable for understanding tumor angiogenesis and metastasis.
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