Role of JAK2–STAT3 in TLR2‐mediated tissue factor expression

Park, Dae-Weon; Lyu, Ji Hyo; Kim, Jinsik; Chin, Haemin; Bae, Yoe‐Sik; Baek, Suk‐Hwan

doi:10.1002/jcb.24472

Cited by 19 publications

(12 citation statements)

References 29 publications

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“…Wang et al highlighted the role of JAK3 in regulation of TLR‐mediated inflammatory cytokine production [Wang et al, ]. Our previous report also showed the importance of JAK2‐STAT3 pathway in TLR2‐mediated tissue factor expression [Park et al, ]. Another example is that STAT1 plays a role in TLR signaling and inflammatory response [Luu et al, ].…”

Section: Discussionmentioning

confidence: 94%

Regulation of PHLDA1 Expression by JAK2-ERK1/2-STAT3 Signaling Pathway

et al. 2015

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Toll-like receptor 2 (TLR2)-mediated signaling cascades and gene regulation are mainly involved in diseases, such as immunity and inflammation. In this study, microarray analysis was performed using bone marrow-derived macrophages (BMDM) and Raw 264.7 cells to identify novel proteins involved in the TLR2-mediated cellular response. We found that pleckstrin homology-like domain family, member 1 (PHLDA1) is a novel gene up-regulated by TLR2 stimulation and determined the unique signaling pathway for its expression. Treatment with TLR2 agonist Pam3 CSK4 increased mRNA, protein, and fluorescence staining of PHLDA1. Induction of PHLDA1 by TLR2 stimulation disappeared from TLR2 KO mice-derived BMDM. Among janus kinase (JAK) family members, JAK2 was involved in TLR2-stimulated PHLDA1 expression. Signal transducer and activator of transcription 3 (STAT3) also participated in PHLDA1 expression downstream of the JAK2. Interestingly, ERK1/2 was an intermediate between JAK2 and STAT3. In silico analysis revealed the presence of highly conserved γ-activated sites within mouse PHLDA1 promoter and confirmed the JAK2-STAT3 pathway is important to Pam3 CSK4 -induced PHLDA1 transcription. These findings suggest that the JAK2-ERK1/2-STAT3 pathway is an important signaling pathway for PHLDA1 expression and that these proteins may play a critical role in eliciting TLR2-mediated immune and inflammatory response.

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Section: Discussionmentioning

confidence: 94%

Regulation of PHLDA1 Expression by JAK2-ERK1/2-STAT3 Signaling Pathway

et al. 2015

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“…In the present study, treatment of the cells with Pam 3 CSK 4 markedly increased the mRNA expression of MCP-1 in a time-dependent manner. TF is a major risk factor for atherosclerosis, and lectin-Lox-1 is also crucial in oxidized-LDL-mediated atherosclerosis (14,16). Therefore, the present study measured changes in the expression levels of these two genes following TLR2 stimulation.…”

Section: Inflammatory Mediators Are Upregulated By Tlr2 Stimulationmentioning

confidence: 97%

“…Among TLRs, TLR2 is also involved in the progression of atheroma. A previous study reported that TLR2 is a receptor for foam cell formation (13,14); therefore, the present study attempted to determine the role of TRIF in TLR2-mediated foam cell formation using the siRNA technique. Compared with the control siRNA-transfected cells, the TRIF-siRNA transfected cells showed decreased mRNA expression of TRIF.…”

Section: Trif Is Involved In Tlr2-induced Foam Cell Formationmentioning

confidence: 99%

TRIF is a regulator of TLR2-induced foam cell formation

Huang¹,

Park²,

Baek³

2016

Molecular Medicine Reports

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The activation of toll-like receptor 2 (TLR2) stimulates foam cell formation, which is a key early event in the process of atherosclerosis. In the present study, the role of toll/interleukin-1 receptor-domain-containing adaptor-inducing interferon-β (TRIF) in TLR2-mediated foam cell formation was investigated, and the importance of monocyte chemoattractant protein‑1 (MCP‑1), tissue factor (TF) and lectin‑like oxidized low‑density lipoprotein receptor‑1 (Lox‑1) were examined. Treatment of Raw 264.7 cells with the TLR2 agonist. Pam3CSK4, increased the gene expression of TRIF in a time‑dependent manner (RT‑PCR). The induced gene expression of TRIF stimulated by TLR2 was not observed in TLR2‑knockout mice‑derived bone marrow‑derived macrophages (BMDMs). Pam3CSK4 increased the mRNA expression of TRIF in the wild‑type BMDMs, but not in the TLR2‑knockout BMDMs. Knockdown of the expression of TRIF using small interfering RNA decreased Pam3CSK4‑induced foam cell formation (combination of oil‑red O and hematoxylin staining), suggesting a role of TRIF. Stimulation of TLR2 increased the expression levels of various genes, which are known to control atherosclerosis, including MCP‑1, TF and Lox‑1. The knockdown of TRIF also attenuated the Pam3CSK4‑induced expression of these genes. In addition, a reduction in TRIF affected the Pam3CSK4‑induced protein expression of MCP‑1 (EIA). Taken together, the results of the present study suggested that TRIF regulated foam cell formation via regulation of the expression levels of MCP‑1, TF and Lox‑1.

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“…11 NF-κB is the molecular target of ROS and is involved in vascular inflammation. 43 Finally, the IL-6 dependent JAK/STAT pathway was examined by a western blot assay. 40 TF, a 47 kDa protein, regulated by the transcription factors, NF-κB and AP-1/c-JUN, is the primary activator of the coagulation cascade.…”

Section: Papermentioning

confidence: 99%

Fine particulate matter induces vascular endothelial activation via IL-6 dependent JAK1/STAT3 signaling pathway

et al. 2016

Toxicol. Res.

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Exposure to PM2.5 has been strongly linked to endothelial dysfunction. However, the underlying mechanism of PM2.5 on the vascular endothelial function is poorly understood. This study examined the toxic effect and underlying mechanism of PM2.5 on human umbilical vein endothelial cells (HUVECs). Decreased cell viability and increased LDH activity were observed in the PM2.5-treated HUVECs in a dose-dependent manner. The production of ROS, MDA, and the inhibition of SOD activity were also triggered by PM2.5 in HUVECs. In addition, PM2.5 increased the intracellular levels of proinflammatory cytokines (IL-6, TNF-a, IL-1β, IL-8 and CRP), cell adhesion molecules (ICAM-1, VCAM-1) and tissue factor (TF), resulted in endothelial activation. For an in-depth study, the protein levels of IL-6, JAK1 and STAT3 were up-regulated significantly, while the expression of JAK2 and SOCS1 were down-regulated gradually in PM2.5-treated HUVECs in a dose-dependent manner. These results show that PM2.5 triggered endothelial activation upregulation of the IL-6 dependent JAK1/STAT3 signaling pathway. This will provide new insights into the toxic effects and mechanisms of cardiovascular diseases triggered by ambient air pollution.

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Role of JAK2–STAT3 in TLR2‐mediated tissue factor expression

Cited by 19 publications

References 29 publications

Regulation of PHLDA1 Expression by JAK2-ERK1/2-STAT3 Signaling Pathway

Regulation of PHLDA1 Expression by JAK2-ERK1/2-STAT3 Signaling Pathway

TRIF is a regulator of TLR2-induced foam cell formation

Fine particulate matter induces vascular endothelial activation via IL-6 dependent JAK1/STAT3 signaling pathway

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