Plasminogen activator inhibitor-1 stimulates macrophage activation through Toll-like Receptor-4

Gupta, Kamlesh Kumar; Xu, Zhi; Castellino, Francis J.; Ploplis, Victoria A.

doi:10.1016/j.bbrc.2016.06.065

Cited by 43 publications

(56 citation statements)

References 27 publications

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“…Recently, two studies have implicated an important role of PAI-1 in macrophages, with one study demonstrating that PAI-1 can regulate macrophage-dependent postoperative adhesion. The second study indicated that PAI-1 can activate macrophages through TLR4 [11, 23], which corroborates our observations that PAI-1 can activate NF-κβ signaling through TLR4. We saw an increase not only in pro-inflammatory cytokines such as IL-6, but also in anti-inflammatory factors such as TGF-β, CCL-17 and CCL-22, which are reported to be downstream targets of NF-κβ signaling.…”

Section: Discussionsupporting

confidence: 89%

“…The role of PAI-1 in cancer has been unclear. Recently, Gupta et al reported that PAI-1 can activate macrophages through Toll-like receptor-4 (TLR4)[11]. Our preliminary data also indicated that the expression of PAI-1 was positively-correlated to levels of secreted TGF-β in human non-small cell lung cancer (NSCLC), which was measured by using immunohistochemistry (IHC) staining.…”

Section: Introductionsupporting

confidence: 55%

“…Since PAI-1 expression was reported to increase in human NSCLC significantly [12], and PAI-1 can activate the macrophages through TLR4[11], we proposed that PAI-1 might be involved in immunosuppression. NSCLC tumors from 60 patients were stained for PAI-1 and TGF-β.…”

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

Plasminogen Activator Inhibitor 1 Promotes Immunosuppression in Human Non-Small Cell Lung Cancers by Enhancing TGF-Β1 Expression in Macrophage

Zhu¹,

Shen²,

Zhu³

et al. 2017

Cell Physiol Biochem

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Background: Plasminogen activator inhibitor-1 (PAI-1) has been regarded as a risk factor for thrombosis and atherosclerosis. Since it has been shown that PAI-1 can activate macrophages through Toll-like receptor-4, we sought to investigate the role of PAI-1 in the tumor microenvironment. Methods: The expression and distribution patterns of PAI-1 and transforming growth factor beta (TGF-β) were measured in 60 non-small cell lung cancer (NSCLC) tumors. A statistical correlation analysis was performed between PAI-1 and TGF-β expression and distribution in each tumor. The distribution of tumor-associated macrophages (TAMs) was also measured and its correlation to PAI-1 levels was analyzed. Levels of secreted CCL-17, CCL-22, IL-6 and TGF-β were measured in cell cultures of human macrophage cell lines THP-1 and U937 treated with PAI-1. Levels of secreted PAI-1 were monitored in cell cultures of human NSCLCs cell lines 95D and A549 treated with TGF-β. Secreted proteins were measured in cell culture supernatants using ELISA. Changes in downstream signaling pathways were investigated using western blot. Results: PAI-1 and TGF-β were found to be overexpressed in human NSCLCs. PAI-1 expression was tightly correlated to TGF-β expression as well as the percentage of TAMs. PAI-1 treatment increased the expression of TAM-associated cytokines and chemokines, including CCL-17, CCL-22, and IL-6. PAI-1 treatment was also observed to enhance TGF-β expression in macrophage cell lines through an IL-6 autocrine/paracrine manner. The effects on TGF-β expression were blocked by NF-κB and STAT3 inhibition. Interestingly, TGF-β also increased levels of secreted PAI-1 in NSCLC cells through SMAD3-dependent signaling, therefore resulting in a feed-forward loop. However, this loop could be blocked by NF-κB, STAT3 and SMAD3 signaling inhibition, as well as treatment with a high concentration of TGF-β. Conclusion: PAI-1 and TGF-β promote NSCLC tumor cells and TAMs and might be valuable targets for cancer immunosuppression.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionsupporting

confidence: 55%

See 1 more Smart Citation

Plasminogen Activator Inhibitor 1 Promotes Immunosuppression in Human Non-Small Cell Lung Cancers by Enhancing TGF-Β1 Expression in Macrophage

Zhu¹,

Shen²,

Zhu³

et al. 2017

Cell Physiol Biochem

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“…The mechanisms through which PAI‐1 specifically modulates fibrosis are complex. They include inhibitory effects on matrix remodeling, proinflammatory effects including macrophage activation and infiltration, possibly in association with cellular senescence as a precipitating factor, and epithelial/endothelial‐to‐mesenchymal transition (EMT) . Regardless of the mechanism, a variety of small‐molecule inhibitors of PAI‐1 have been developed and investigated, with the majority of these inhibitors either targeting the PAI‐1 binding domain to tPA/uPA or designed to induce a conformational change in PAI‐1 to convert it to its inactive form .…”

mentioning

confidence: 99%

Transcriptomic Analysis of Cellular Pathways in Healing Flexor Tendons of Plasminogen Activator Inhibitor 1 (PAI‐1/Serpine1) Null Mice

Freeberg

Easa

Lillis

et al. 2019

Journal Orthopaedic Research

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Injuries to flexor tendons can be complicated by fibrotic adhesions, which severely impair the function of the hand. Plasminogen activator inhibitor 1 (PAI‐1/SERPINE1), a master suppressor of fibrinolysis and protease activity, is associated with adhesions. Here, we used next‐generation RNA sequencing (RNA‐Seq) to assess genome‐wide differences in messenger RNA expression due to PAI‐1 deficiency after zone II flexor tendon injury. We used the ingenuity pathway analysis to characterize molecular pathways and biological drivers associated with differentially expressed genes (DEG). Analysis of hundreds of overlapping and DEG in PAI‐1 knockout (KO) and wild‐type mice (C57Bl/6J) during tendon healing revealed common and distinct biological processes. Pathway analysis identified cell proliferation, survival, and senescence, as well as chronic inflammation as potential drivers of fibrotic healing and adhesions in injured tendons. Importantly, we identified the activation of PTEN signaling and the inhibition of FOXO1‐associated biological processes as unique transcriptional signatures of the healing tendon in the PAI‐1/Serpine1 KO mice. Further, transcriptomic differences due to the genetic deletion of PAI‐1 were mechanistically linked to PI3K/Akt/mTOR, PKC, and MAPK signaling cascades. These transcriptional observations provide novel insights into the biological roles of PAI‐1 in tendon healing and could identify therapeutic targets to achieve scar‐free regenerative healing of tendons. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:43–58, 2020

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“…51 PAI-1 knockdown attenuated LPSinduced increases in TLR4, MD-2, MyD88, TNF-a, IL-1b, and NF-jB expression in macrophages, while vector-driven PAI-1 overexpression enhanced these responses. 52,53 Although the mechanism is unclear, it appears that PAI-1 regulates the endotoxin-stimulated TLR4/MD-2 inflammatory pathway, at least in cells of the macrophage lineage.…”

mentioning

confidence: 89%

Integration of Canonical and Noncanonical Pathways in TLR4 Signaling: Complex Regulation of the Wound Repair Program

McKeown‐Longo

Higgins

2017

Advances in Wound Care

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Plasminogen activator inhibitor-1 stimulates macrophage activation through Toll-like Receptor-4

Cited by 43 publications

References 27 publications

Plasminogen Activator Inhibitor 1 Promotes Immunosuppression in Human Non-Small Cell Lung Cancers by Enhancing TGF-Β1 Expression in Macrophage

Plasminogen Activator Inhibitor 1 Promotes Immunosuppression in Human Non-Small Cell Lung Cancers by Enhancing TGF-Β1 Expression in Macrophage

Transcriptomic Analysis of Cellular Pathways in Healing Flexor Tendons of Plasminogen Activator Inhibitor 1 (PAI‐1/Serpine1) Null Mice

Integration of Canonical and Noncanonical Pathways in TLR4 Signaling: Complex Regulation of the Wound Repair Program

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