Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
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Target Concepts:
Gene/Protein
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Query: UNIPROT:P05231 (
interleukin-6
)
23,907
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Bone marrow angiogenesis plays an important role in the pathogenesis and progression in multiple myeloma. Recent studies have shown that proteasome inhibitor bortezomib (Velcade, formerly PS-341) can overcome conventional drug resistance in vitro and in vivo; however, its antiangiogenic activity in the bone marrow milieu has not yet been defined. In the present study, we examined the effects of bortezomib on the angiogenic phenotype of multiple myeloma patient-derived endothelial cells (MMEC). At clinically achievable concentrations, bortezomib inhibited the proliferation of MMECs and human umbilical vein endothelial cells in a dose-dependent and time-dependent manner. In functional assays of angiogenesis, including chemotaxis, adhesion to fibronectin, capillary formation on Matrigel, and chick embryo chorioallantoic membrane assay, bortezomib induced a dose-dependent inhibition of angiogenesis. Importantly, binding of MM.1S cells to MMECs triggered multiple myeloma cell proliferation, which was also abrogated by bortezomib in a dose-dependent fashion. Bortezomib triggered a dose-dependent inhibition of vascular endothelial growth factor (VEGF) and
interleukin-6
(
IL-6
) secretion by the MMECs, and reverse transcriptase-PCR confirmed drug-related down-regulation of VEGF,
IL-6
, insulin-like growth factor-I,
Angiopoietin 1
(
Ang1
), and Ang2 transcription. These data, therefore, delineate the mechanisms of the antiangiogenic effects of bortezomib on multiple myeloma cells in the bone marrow milieu.
...
PMID:Bortezomib mediates antiangiogenesis in multiple myeloma via direct and indirect effects on endothelial cells. 1639 31
The regulation of endothelial cell (EC) permeability is critical for the physiological homeostasis of blood vessels and tissues. The elevation of pro-inflammatory cytokines is highly associated with lesions, such as the increased vascular permeability of diabetic retinas. We have previously reported that
interleukin-6
(
IL-6
) increases EC permeability through the downregulation of tight junction protein expression.
Angiopoietin 1
(
Ang1
) has an anti-permeability function, but the effect of
Ang1
on vascular permeability induced by inflammatory cytokines is unclear. In the present study, we investigated the effect of
Ang1
on
IL-6
-induced EC permeability and its underlying molecular mechanisms. We demonstrated that
Ang1
inhibited the
IL-6
-induced increase in EC permeability by inhibiting the reductions in the levels of tight junction protein ZO-1 and occludin, which was related to the decrease in vascular endothelial growth factor (VEGF) secretion through the inhibition of STAT3 activation by
Ang1
. Mechanistically,
Ang1
induced the dissociation of the tyrosine phosphatase SHP-1 from the Tie2 receptor and increased the binding of SHP-1 to JAK1, JAK2, and STAT3, which are
IL-6
downstream signaling proteins. We conclude that SHP-1 plays an important role in the
Ang1
-induced inhibition of JAK/STAT3 signaling. These results provide evidence for a potential beneficial role of
Ang1
in suppressing the vascular permeability induced by the pro-inflammatory cytokine
IL-6
in diabetic retinopathy.
...
PMID:Angiopoietin 1 attenuates interleukin-6-induced endothelial cell permeability through SHP-1. 3142 82
