Fetal Fibronectin Signaling Induces Matrix Metalloproteases and Cyclooxygenase-2 (COX-2) in Amnion Cells and Preterm Birth in Mice

Mogami, Haruta; Kishore, A. Hari; Shi, Haolin; Keller, Patrick W.; Akgul, Yucel; Word, R. Ann

doi:10.1074/jbc.m112.424366

Cited by 45 publications

(33 citation statements)

References 60 publications

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“…Further, thrombin-induced increases in these TLR4 target genes were not mitigated by endotoxin removal, and endotoxin-free recombinant thrombin also increased MMP1 and COX2. Interestingly, we found that thrombin also stimulated release of fibronectin from its cellbound fibrillar form to its soluble form, which is known to activate TLR4 (23). Thrombin-induced release of fibronectin occurred even in epithelial cells with nonfunctioning TLR4 complexes, indicating that thrombin-induced activation of MMP1 was not required.…”

Section: Discussionmentioning

confidence: 64%

“…Furthermore, thrombin treatment (4 units/ml (36 nM) ϫ 48 h) dramatically increased soluble fibronectin in conditioned media from both amnion mesenchymal cells (TLR4-responsive) and epithelial cells which do not express functional TLR4 (Fig. 8B) (23). Further, in contrast with mesenchymal cells, thrombin-induced release of fibronectin was not accompanied by increased expression of COX2 and MMP1 in epithelial cells (data not shown).…”

Section: Up-regulation Of Mmp9 Mrna Is Mediated Via Par-1-tomentioning

confidence: 83%

“…In contrast with MMP-9, thrombin-induced increases in MMP1 and COX2 in amnion mesenchymal cells were not mediated by activation of PAR-1. Our previous results indicated that the extra domain A of fetal fibronectin upregulated MMP-1 and COX-2 through activation of TLR4 in amnion mesenchymal cells (23). Hence, we suspected that thrombin also sent signals via TLR4.…”

Section: Discussionmentioning

confidence: 99%

“…Evidence That Up-regulation of MMP-1 and COX2 Is Mediated via Toll-like Receptor-4-Previously, we found that fetal fibronectin up-regulated MMP-1 and COX-2 mRNA and enzymatic activity in mesenchymal cells through extra domain A-mediated activation of TLR4 (23). To determine whether thrombin signals through TLR4, the effect of a TLR4 neutralizing antibody on thrombin-induced increases in MMP1 and COX2 mRNA was determined.…”

Section: Up-regulation Of Mmp9 Mrna Is Mediated Via Par-1-tomentioning

confidence: 99%

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Effect of Thrombin on Human Amnion Mesenchymal Cells, Mouse Fetal Membranes, and Preterm Birth

Mogami

Keller

Shi

et al. 2014

Journal of Biological Chemistry

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Background: Bleeding during pregnancy is a risk factor for premature rupture of the fetal membranes. Results: Thrombin causes preterm birth in mice and activates PAR-1 and TLR4 to increase MMPs and COX-2. Conclusion: Thrombin acts through multiple mechanisms to increase MMPs and PGE 2 in amnion. Significance: Thrombin plays a pivotal role in the pathogenesis of preterm labor and rupture of the membranes.

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Section: Discussionmentioning

confidence: 64%

Section: Up-regulation Of Mmp9 Mrna Is Mediated Via Par-1-tomentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Up-regulation Of Mmp9 Mrna Is Mediated Via Par-1-tomentioning

confidence: 99%

See 2 more Smart Citations

Effect of Thrombin on Human Amnion Mesenchymal Cells, Mouse Fetal Membranes, and Preterm Birth

Mogami

Keller

Shi

et al. 2014

Journal of Biological Chemistry

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“…9,17,18 The EDA domain of fibronectin can activate TLR4 signaling as either the individual domain, proteolytic fragment or in the context of the intact molecule. 19,20 Being responsible for matrix synthesis, assembly, and turnover, stromal fibroblasts are in constant dialogue with the fibronectin matrix in its polymerized and fragmented forms. Changes in tissue mechanical forces have been shown to cause the structurally labile fibronectin type III (FnIII) domains to unfold, revealing otherwise hidden bioactive sites.…”

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confidence: 99%

TLR4 Ligands Selectively Synergize to Induce Expression of IL-8

Valenty

Longo

Horzempa

et al. 2017

Advances in Wound Care

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Objective: Dysfunctional remodeling of the extracellular matrix contributes to the formation of TLR-dependent feed forward loops that drive chronic inflammation. We have previously shown that two Type III domains of Fibronectin, FnEDA and FnIII-1c, cooperate to induce the synergistic release of interleukin 8 (IL-8) from dermal fibroblasts. We now identify steps in the TLR4 pathway where synergy can be demonstrated as well as additional kinases functioning in fibronectin activation of TLR4 signaling. We also evaluate the ligand and cell-type specificity of this synergistic response. Approach: FnEDA, FnIII-1c, and lipopolysaccharide (LPS)-induced genes in fibroblasts were analyzed by a quantitative reverse transcription-polymerase chain reaction (qPCR) and protein was measured by an enzyme-linked immunosorbent assay (ELISA). Kinases functioning in gene expression were identified by using specific inhibitors. Activated TLR4-dependent effector molecules were identified by cell fractionation and Western blot and quantified by image analysis. Results: The addition of FnEDA and FnIII-1c to dermal fibroblasts resulted in a synergistic increase in the expression of IL-8, tumor necrosis factor alpha (TNF-a), and vascular cell adhesion molecule (VCAM-1). Synergy between these domains was detected at the level of nuclear factor kappa-light chain enhancer of activated B cells (NF-jB) and inhibitor of kappa B kinase (IKK) activation. Induction of IL-8 by fibronectin ligands was partially attenuated in the presence of inhibitors to either epidermal growth factor receptor or Src kinases. FnIII-1c also synergized with LPS to induce IL-8 in dermal fibroblasts, whereas the combined effect of FnEDA and LPS on IL-8 synthesis was additive. In contrast, synergistic responses to these ligands were not observed in THP-1 monocytic cells. Innovation: The data suggest that chronic inflammation may be driven by matrix-and pathogen-derived TLR4 ligands that work in synergy to promote an exuberant innate response. Conclusion: The data suggest that the molecular mechanism underlying synergistic responses to TLR4 ligands lies upstream of IKK activation, likely in the molecular composition of the TLR4 receptor complex that assembles in response to each ligand. In addition, synergistic responses to TLR4 activation may be both cell-type and ligand specific. Keywords: fibronectin, TLR4, IL-8, inflammation, LPS INTRODUCTIONProlonged inflammation in response to injury is a contributory factor to the development of chronic wounds. Extracellular matrix (ECM)- fibronectin has also been shown to promote fibro-inflammatory responses in several mouse models. 9,17,18 The EDA domain of fibronectin can activate TLR4 signaling as either the individual domain, proteolytic fragment or in the context of the intact molecule. 19,20 Being responsible for matrix synthesis, assembly, and turnover, stromal fibroblasts are in constant dialogue with the fibronectin matrix in its polymerized and fragmented forms. Changes in tissue mechanical forces have been shown to caus...

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Targeting Toll‐like receptor‐4 to tackle preterm birth and fetal inflammatory injury

et al. 2020

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Every year, 15 million pregnancies end prematurely, resulting in more than 1 million infant deaths and long-term health consequences for many children. The physiological processes of labour and birth involve essential roles for immune cells and proinflammatory cytokines in gestational tissues. There is compelling evidence that the mechanisms underlying spontaneous preterm birth are initiated when a premature and excessive inflammatory response is triggered by infection or other causes. Exposure to pro-inflammatory mediators is emerging as a major factor in the 'fetal inflammatory response syndrome' that often accompanies preterm birth, where unscheduled effects in fetal tissues interfere with normal development and predispose to neonatal morbidity. Toll-like receptors (TLRs) are critical upstream gatekeepers of inflammatory activation. TLR4 is prominently involved through its ability to sense and integrate signals from a range of microbial and endogenous triggers to provoke and perpetuate inflammation. Preclinical studies have identified TLR4 as an attractive pharmacological target to promote uterine quiescence and protect the fetus from inflammatory injury. Novel smallmolecule inhibitors of TLR4 signalling, specifically the non-opioid receptor antagonists (+)-naloxone and (+)-naltrexone, are proving highly effective in animal models for preventing preterm birth induced by bacterial mimetic LPS, heat-killed Escherichia coli, or the TLR4-dependent pro-inflammatory lipid, platelet-activating factor (PAF). Here, we summarise the rationale for targeting TLR4 as a master regulator of inflammation in fetal and gestational tissues, and the potential utility of TLR4 antagonists as candidates for preventative and therapeutic application in preterm delivery and fetal inflammatory injury.

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Fetal Fibronectin Signaling Induces Matrix Metalloproteases and Cyclooxygenase-2 (COX-2) in Amnion Cells and Preterm Birth in Mice

Cited by 45 publications

References 60 publications

Effect of Thrombin on Human Amnion Mesenchymal Cells, Mouse Fetal Membranes, and Preterm Birth

Effect of Thrombin on Human Amnion Mesenchymal Cells, Mouse Fetal Membranes, and Preterm Birth

TLR4 Ligands Selectively Synergize to Induce Expression of IL-8

Targeting Toll‐like receptor‐4 to tackle preterm birth and fetal inflammatory injury

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