Conditional Vascular Cell Adhesion Molecule 1 Deletion in Mice

Koni, Pandelakis A.; Joshi, Sunil; Temann, Ulla-Angela; Olson, Dian; Burkly, Linda C.; Flavell, Richard A.

doi:10.1084/jem.193.6.741

Cited by 449 publications

(545 citation statements)

References 76 publications

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“…This discrepancy might result from the differences in the Cre promoter used for generation of STAT3-deficient mice, Tie2 vs Lck promoters. Tie2 gene promoter drives Cre expression in bone marrow and endothelial cells (51), while Lck gene promoter drives it in immature T cells (24). Tissue-specific disruption of STAT3 in bone marrow cells of Tie2-Cre/STAT3 flox/flox mice during hematopoiesis was reported to cause death within 4 -6 wk after birth with Crohn's disease-like conditions including dramatic expansion of myeloid lineages, and massive infiltration of the intestine with neutrophils, macrophages, and eosinophils (52).…”

Section: Discussionmentioning

confidence: 99%

STAT3 Is Indispensable to IL-27-Mediated Cell Proliferation but Not to IL-27-Induced Th1 Differentiation and Suppression of Proinflammatory Cytokine Production

Owaki

Asakawa

Morishima

et al. 2008

The Journal of Immunology

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IL-27, a member of the IL-6/IL-12 family, activates both STAT1 and STAT3 through its receptor, which consists of WSX-1 and gp130 subunits, resulting in augmentation of Th1 differentiation and suppression of proinflammatory cytokine production. In the present study, we investigated the role of STAT3 in the IL-27-mediated immune functions. IL-27 induced phosphorylation of STAT1, -2, -3 and -5 in wild-type naive CD4+ T cells, but failed to induce that of STAT3 and STAT5 in STAT3-deficient cohorts. IL-27 induced not only proinflammatory responses including up-regulation of ICAM-1, T-box expressed in T cells, and IL-12Rβ2 and Th1 differentiation, but also anti-inflammatory responses including suppression of proinflammatory cytokine production such as IL-2, IL-4, and IL-13 even in STAT3-deficient naive CD4+ T cells. In contrast, IL-27 augmented c-Myc and Pim-1 expression and induced cell proliferation in wild-type naive CD4+ T cells but not in STAT3-deficient cohorts. Moreover, IL-27 failed to activate STAT3, augment c-Myc and Pim-1 expression, and induce cell proliferation in pro-B BaF/3 transfectants expressing mutant gp130, in which the putative STAT3-binding four Tyr residues in the YXXQ motif of the cytoplasmic region was replaced by Phe. These results suggest that STAT3 is activated through gp130 by IL-27 and is indispensable to IL-27-mediated cell proliferation but not to IL-27-induced Th1 differentiation and suppression of proinflammatory cytokine production. Thus, IL-27 may be a cytokine, which activates both STAT1 and STAT3 through distinct receptor subunits, WSX-1 and gp130, respectively, to mediate its individual immune functions.

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Section: Discussionmentioning

confidence: 99%

STAT3 Is Indispensable to IL-27-Mediated Cell Proliferation but Not to IL-27-Induced Th1 Differentiation and Suppression of Proinflammatory Cytokine Production

Owaki

Asakawa

Morishima

et al. 2008

The Journal of Immunology

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“…HSP27 stop transgenic mice for conditional overexpression of HSP27 were generated at the Shanghai Research Center for Model Organisms (Shanghai, China) through a service contract. To obtain mice with EC-targeted overexpression of HSP27, HSP27 stop mice were crossed with Tek-Cre mice (43), in which the Cre-mediated recombination is restricted to ECs. C57BL/6J mice were used as matched WT controls.…”

Section: Methodsmentioning

confidence: 99%

Endothelium-targeted overexpression of heat shock protein 27 ameliorates blood–brain barrier disruption after ischemic brain injury

Shi

Jiang

Zhang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

114

132

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The damage borne by the endothelial cells (ECs) forming the blood–brain barrier (BBB) during ischemic stroke and other neurological conditions disrupts the structure and function of the neurovascular unit and contributes to poor patient outcomes. We recently reported that structural aberrations in brain microvascular ECs—namely, uncontrolled actin polymerization and subsequent disassembly of junctional proteins, are a possible cause of the early onset BBB breach that arises within 30–60 min of reperfusion after transient focal ischemia. Here, we investigated the role of heat shock protein 27 (HSP27) as a direct inhibitor of actin polymerization and protectant against BBB disruption after ischemia/reperfusion (I/R). Using in vivo and in vitro models, we found that targeted overexpression of HSP27 specifically within ECs—but not within neurons—ameliorated BBB impairment 1–24 h after I/R. Mechanistically, HSP27 suppressed I/R-induced aberrant actin polymerization, stress fiber formation, and junctional protein translocation in brain microvascular ECs, independent of its protective actions against cell death. By preserving BBB integrity after I/R, EC-targeted HSP27 overexpression attenuated the infiltration of potentially destructive neutrophils and macrophages into brain parenchyma, thereby improving long-term stroke outcome. Notably, early poststroke administration of HSP27 attached to a cell-penetrating transduction domain (TAT-HSP27) rapidly elevated HSP27 levels in brain microvessels and ameliorated I/R-induced BBB disruption and subsequent neurological deficits. Thus, the present study demonstrates that HSP27 can function at the EC level to preserve BBB integrity after I/R brain injury. HSP27 may be a therapeutic agent for ischemic stroke and other neurological conditions involving BBB breakdown.

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“…Only 6% of VCAM-1 4D/4D pups survive in the C57BL/6 strain, too few to conduct meaningful studies. Conditional VCAM-1 knockout mice, which could offer another way to circumvent the problem of developmental lethality, have been described (17,18) but have not yet been tested in atherosclerosis models. It is possible that inducible and/or tissue-specific VCAM-1 knockouts may provide informative data when crossed with the LDL receptor knockout mutants.…”

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confidence: 99%