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PMID:23148224
| Citation |
'Bauer, EM, Shapiro, R, Billiar, TR and Bauer, PM (2012) High Mobility Group Box-1 Inhibits Human Pulmonary Artery Endothelial Cell Migration via a TLR4 and IRF3-dependent Mechanism(s). J. Biol. Chem. ' |
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| Abstract |
In pulmonary hypertension the loss of precapillary arterioles results from vascular injury causing endothelial dysfunction. Endothelial cell migration and proliferation are critical for vascular regeneration. This study focused on the effect of high mobility group box 1 protein (HMGB1) on these critical processes. HMGB1 had no effect on human pulmonary artery endothelial cell (HPAEC) proliferation. In contrast, treatment of HPAEC with HMGB1 dose-dependently inhibited VEGF-stimulated HPAEC migration. The effect of HMGB1 on HPAEC migration was TLR4-dependent since it was reversed by TLR4 siRNA or TLR4 neutralizing antibody. Exposure of HPAEC to hypoxia caused translocation and release of HMGB1 and inhibition of HPAEC migration. The effect of hypoxia on HPAEC migration was mediated by HMGB1 since HMGB1 neutralizing antibody but not control IgG restored HPAEC migration. Likewise, TLR4 siRNA but not control siRNA reversed the inhibitory effect of hypoxia in HPAEC. The canonical TLR4 signaling pathway requires the adaptor protein MyD88 and leads to downstream NFκB activation. Interestingly, HMGB1 failed to stimulate NFκB translocation to the nucleus, but instead activated an alternative pathway characterized by activation of interferon response factor 3 (IRF3). This was in contrast to human umbilical vein endothelial cells in which HMGB1 stimulated nuclear translocation of NFκB but not IRF3. IRF3 siRNA, but not MyD88 siRNA reversed the inhibitory effect of HMGB1 on HPAEC migration. These data demonstrate that HMGB1 inhibits HPAEC migration, a critical process for vascular regeneration, via TLR4- and IRF-3-dependent mechanisms. |
| Links |
PubMed Online version:10.1074/jbc.M112.434142 |
| Keywords |
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| edit table |
Significance
Annotations
| Gene product | Qualifier | GO Term | Evidence Code | with/from | Aspect | Extension | Notes | Status |
|---|---|---|---|---|---|---|---|---|
|
involved_in |
GO:0043537: negative regulation of blood vessel endothelial cell migration |
ECO:0000314: direct assay evidence used in manual assertion |
P |
Seeded From UniProt |
complete | |||
| GO:0043537: negative regulation of blood vessel endothelial cell migration |
ECO:0000314: |
P |
Figure 2 shows that HMGB1 inhibits HPAEC migration, which is a critical process for vascular regeneration. |
complete | ||||
See also
References
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