Shear stress‐induced Ets‐1 modulates protease inhibitor expression in microvascular endothelial cells

Milkiewicz, Małgorzata; Uchida, Cassandra; Gee, Eric; Fudalewski, Tomasz; Haas, Tara L.

doi:10.1002/jcp.21526

Cited by 32 publications

(26 citation statements)

References 54 publications

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“…22,[30][31][32] Furthermore, MEK/ERK pathway has a well-established role in propagating TCR signals, leading to the activation of c-ETS transcription factors. 33 Interestingly, CsA, an inhibitor of AP-1, NFAT, and NF-B, and the MEK/ERK inhibitor PD98059 markedly decreased miR-146a expression upon TCR stimulation, thus suggesting that transcription factors sensitive to these inhibitors modulate miR-146a transcription.…”

Section: Discussionmentioning

confidence: 97%

An emerging player in the adaptive immune response: microRNA-146a is a modulator of IL-2 expression and activation-induced cell death in T lymphocytes

Curtale¹,

Citarella²,

Carissimi³

et al. 2010

Blood

268

225

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Activation of the T cell-mediated immune response has been associated with changes in the expression of specific microRNAs (miRNAs). However, the role of miRNAs in the development of an effective immune response is just beginning to be explored. This study focuses on the functional role of miR-146a in T lymphocyte-mediated immune response and provides interesting clues on the transcriptional regulation of miR146a during T-cell activation. We show that miR-146a is low in human naive T cells and is abundantly expressed in human memory T cells; consistently, miR-146a is induced in human primary T lymphocytes upon T-cell receptor (TCR) stimulation. Moreover, we identified NF-kB and c-ETS binding sites as required for the induction of miR-146a transcription upon TCR engagement. Our results demonstrate that several signaling pathways, other than inflammation, are influenced by miR-146a. In particular, we provide experimental evidence that miR-146a modulates activation-induced cell death (AICD), acting as an antiapoptotic factor, and that Fasassociated death domain (FADD) is a target of miR-146a. Furthermore, miR146a enforced expression impairs both activator protein 1 (AP-1) activity and interleukin-2 (IL-2) production induced by TCR engagement, thus suggesting a role of this miRNA in the modulation of adaptive immunity. (Blood. 2010;115: 265-273) IntroductionDuring adaptive immune response T-cell receptor (TCR) engagement by the antigen triggers a signal cascade, which leads to the activation of 3 main transcription factors: AP-1, NF-kB, and NFAT, critically involved in cytokine production. In particular, these transcription factors regulate the expression of early cytokines, especially interleukin-2 (IL-2), that mediate the lymphocytic "clonal expansion" phase. 1 Once the foreign threat has been overcome and T lymphocytes have served their effector functions, they must be removed. The death of activated lymphocytes serves to limit the immune response by killing cells that are no longer needed or cells that may have developed the potential to recognize and generate a response to selfantigens. Deregulation of apoptotic pathways in T cells may lead to a spectrum of diseases, including autoimmune diseases and proliferative disorders. 2,3 MicroRNAs (miRNAs) recently came into focus as a novel class of posttranscriptional regulatory elements. They are small endogenous noncoding RNAs that repress mRNA translation by base pairing to 3Ј untranslated region (3ЈUTR) of the target genes. In particular, miRNAs are powerful tools that can be promptly expressed by the cell and have the potential to coordinately regulate a large number of different target genes. This suggests that they can be optimal candidates for the control of immune response, a process involving large regulative networks and fine prompt modulation.The first indication that miRNAs are involved in immunity has emerged by studies showing the selective expression of miR-223 in bone marrow and the involvement of miR-223, miR-155, and miR-146a in the differentiation ...

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Section: Discussionmentioning

confidence: 97%

An emerging player in the adaptive immune response: microRNA-146a is a modulator of IL-2 expression and activation-induced cell death in T lymphocytes

Curtale¹,

Citarella²,

Carissimi³

et al. 2010

Blood

268

225

View full text Add to dashboard Cite

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“…Ets-1 dominant negative constructs injected in the eye completely blocked this function. Its expression is further upregulated by VEGF and shear stress which in turn increase Ang-2 expression [130,131]. Ang-2 expression is also regulated by the transcription factor FOXO1.…”

Section: Angiopoietin-2 Functions During Inflammationmentioning

confidence: 99%

The role of the Angiopoietins in vascular morphogenesis

2009

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The Angiopoietin/Tie system acts as a vascular specific ligand/receptor system to control endothelial cell survival and vascular maturation. The Angiopoietin family includes four ligands (Angiopoietin-1, Angiopoietin-2 and Angiopoietin-3/4) and two corresponding tyrosine kinase receptors (Tie1 and Tie2). Ang-1 and Ang-2 are specific ligands of Tie2 binding the receptor with similar affinity. Tie2 activation promotes vessel assembly and maturation by mediating survival signals for endothelial cells and regulating the recruitment of mural cells. Ang-1 acts in a paracrine agonistic manner inducing Tie2 phosphorylation and subsequent vessel stabilization. In contrast, Ang-2 is produced by endothelial cells and acts as an autocrine antagonist of Ang-1-mediated Tie2 activation. Ang-2 thereby primes the vascular endothelium to exogenous cytokines and induces vascular destabilization at higher concentrations. Ang-2 is strongly expressed in the vasculature of many tumors and it has been suggested that Ang-2 may act synergistically with other cytokines such as vascular endothelial growth factor to promote tumor-associated angiogenesis and tumor progression. The better mechanistic understanding of the Ang/Tie system is gradually paving the way toward the rationale exploitation of this vascular signaling system as a therapeutic target for neoplastic and non-neoplastic diseases.

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“…Shear stress-dependent regulation was, at least partially, induced by VEGF expression. 105,117,120,124 Fluid forces generated by shear stress may also attenuate endothelial cell sprouting in a nitric oxide-dependent manner. Interstitial flow directs cell sprouting and cell morphology and therefore regulates capillary tube formation.…”

Section: Shear Stressmentioning

confidence: 99%