Thrombin induced secretion of macrophage migration inhibitory factor (MIF) and its effect on nuclear signaling in endothelium

Wadgaonkar, Raj; Somnay, Kaumudi; Garcia, Joe G.N.

doi:10.1002/jcb.21928

Cited by 25 publications

(30 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although studies diverge in their conclusions regarding the direct role of MAPKs, such as p38, in endothelial cell adhesion molecule expression (45)(46)(47), there is evidence that endothelial cell NF-kB activity can be enhanced via the actions of MAPKs (22,23). For example, MIF and ERK MAPK have each been shown to amplify thrombin-induced NF-kB transcriptional activity in endothelial cells (22,23).…”

Section: Discussionmentioning

confidence: 99%

“…For example, MIF and ERK MAPK have each been shown to amplify thrombin-induced NF-kB transcriptional activity in endothelial cells (22,23). Also, p38 inhibition has been shown to attenuate NF-kB DNA binding in stimulated HUVECs (22,23).…”

Section: Discussionmentioning

confidence: 99%

“…Endothelial expression of VCAM-1, IL-8, and MCP-1 are facilitated by ERK and p38 MAPK activation (19)(20)(21)(22). Moreover, MIF has been shown to contribute to thrombin-induced ERK(1/2) MAPK activation in endothelial cells and to induce migration and tube formation via activation of the PI3K/Akt pathway (23,24). However, it is unknown whether these effects extend to adhesion molecule expression.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Macrophage Migration Inhibitory Factor Increases Leukocyte–Endothelial Interactions in Human Endothelial Cells via Promotion of Expression of Adhesion Molecules

Cheng

McKeown

Santos

et al. 2010

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Macrophage Migration Inhibitory Factor Increases Leukocyte–Endothelial Interactions in Human Endothelial Cells via Promotion of Expression of Adhesion Molecules

Cheng

McKeown

Santos

et al. 2010

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…Thrombin induces the release of a host of proinflammatory cytokines from endothelial cells, mural cells, epithelial cells, adipocytes, and immune cells. [21][22][23] It is chemotactic for monocytes and neutrophils, induces expression of adhesion molecules, and promotes release of growth factors and chemokines from platelets. Thrombin directly activates both C3 and C5, 10,24 and modulates innate immune responses by altering cytokine secretion and receptor expression by antigen-presenting cells.…”

Section: Thrombin Factor Xa and The Protease-activated Receptorsmentioning

confidence: 99%

Coagulation and innate immune responses: can we view them separately?

Delvaeye

Conway

2009

Blood

266

210

View full text Add to dashboard Cite

The horseshoe crab is often referred to as a "living fossil," representative of the oldest classes of arthropods, almost identical to species in existence more than 500 million years ago. Comparative analyses of the defense mechanisms used by the horseshoe crab that allowed it to survive mostly unchanged throughout the millennia reveal a common ancestry of the coagulation and innate immune systems that are totally integrated-indeed, almost inseparable. In human biology, we traditionally view the hemostatic pathways and those regulating innate immune responses to infections and tissue damage as entirely separate entities. But are they? The last couple of decades have revealed a remarkable degree of interplay between these systems, and the linking cellular and molecular mechanisms are rapidly being delineated. In this review, we present some of the major points of intersection between coagulation and innate immunity. We attempt to highlight the potential impact of these findings by identifying recently established paradigms that will hopefully result in the emergence of new strategies to treat a range of inflammatory and hemostatic disorders. IntroductionThe most menacing challenge to survival that is faced by organisms throughout the animal kingdom is invasion by infections and foreign antigens-events that are frequently accompanied by trauma or a wound. Organisms have thus necessarily developed a variety of effective means to restrict and to fight infections, to contain wounds by limiting bleeding with clot formation, and to rapidly initiate healing. The coexistence of thrombosis with inflammatory responses supports the notion that common molecular mechanisms regulate these complex biologic systems. The last couple of decades have seen major progress in identifying cellular and molecular links between these systems.In this review, we consider some of the key pathways involved in hemostasis, innate immunity, and inflammation, and provide recent data that demonstrate how they are integrated. The interactions are multiple and complex, and present new challenges to identify those that are clinically relevant, with the promise of discovering novel and more effective therapies for a range of diseases. CoagulationThe coagulation system is characterized by the sequential, rapid, and highly localized activation of a series of serine proteases, culminating in the generation of thrombin, with subsequent conversion of fibrinogen into a fibrin clot. Tissue factor (TF) is the key initiator of coagulation (reviewed in Mackman 1 ), and is expressed primarily by subendothelial mural cells and adventitial fibroblasts in and around the vessel wall. Somewhat controversial, it may also be expressed at low levels by monocytes and neutrophils, and found circulating in microparticles and in a soluble form. 2 With vascular endothelial cell damage, TF is exposed to the circulation, and complexes with factor VII/VIIa, initiating activation of factors IX and X. Factor Xa converts prothrombin to thrombin in sufficient quantities to activat...

show abstract

“…[43][44][45][46] ERK1/2 activation has been shown to be activated through both G i (␤␥)-phosphatidylinositol 3-kinase and G q pathways. 47 We examined the effects of i1 versus i3 PAR1 pepducins on ERK1/2 activation in the A549 lung adenocarcinoma cell line.…”

Section: Targeting Par1 G-protein Signaling Using Pepducin Technologymentioning

confidence: 99%

Targeting Protease-Activated Receptor-1 with Cell-Penetrating Pepducins in Lung Cancer

Cisowski

O’Callaghan

Kuliopulos

et al. 2011

The American Journal of Pathology

View full text Add to dashboard Cite

Protease-activated receptors (PARs) are G-proteincoupled receptors that are activated by proteolytic cleavage and generation of a tethered ligand. High PAR1 expression has been documented in a variety of invasive cancers of epithelial origin. In the present study, we investigated the contribution of the four PAR family members to motility of lung carcinomas and primary tumor samples from patients. We found that of the four PARs, only PAR1 expression was highly increased in the lung cancer cell lines. Primary lung cancer cells isolated from patient lung tumors migrated at a 10-to 40-fold higher rate than epithelial cells isolated from nonmalignant lung tissue. Cellpenetrating pepducin inhibitors were generated against the first (i1) and third (i3) intracellular loops of PAR1 and tested for their ability to inhibit PAR1-driven migration and extracellular regulated kinase (ERK)1/2 activity. The PAR1 pepducins showed significant inhibition of cell migration in both primary and established cell lines similar to silencing of PAR1 expression with short hairpin RNA (shRNA). Unlike i1 pepducins, the i3 loop pepducins were effective inhibitors of PAR1-mediated ERK activation and tumor growth. Comparable in efficacy with Bevacizumab, monotherapy with the PAR1 i3 loop pepducin P1pal-7 provided significant 75% inhibition of lung tumor growth in nude mice. We identify the PAR1-ERK1/2 pathway as a feasible target for therapy in lung cancer. Lung cancer is the leading cause of cancer deaths in the United States and worldwide, and is the second most common cancer overall. 1 The majority of patients eventually develop distant metastases, which leads to substantial morbidity and mortality. Currently available chemotherapeutic regimens for the treatment of non-small-cell lung cancer (NSCLC) include combinations of cisplatin or carboplatin, and etoposide, paclitaxel, docetaxel, gemcitabine, vinorelbin, and irinotecan. These regimens are generally not curative and may confer modest prolongation of life and symptomatic relief. 2,3 More recently, targeted therapies have become available for the treatment of lung cancer. These include small molecules and antibodies that target epidermal growth factor receptor and vascular endothelial growth factor receptor. However, the currently available molecular therapies still result in relatively modest prolongation of median and overall survival, pointing to the necessity for developing more effective treatment modalities for patients with advanced NSCLC.Emerging evidence has identified protease activated receptor-1 (PAR1) as a promising target to impact tumor progression, metastasis, and angiogenesis in a variety of cancers including breast, ovarian, melanoma, prostate, and colon cancer. 4 -7 However, the role of PAR1 and the other PAR family members in lung cancer is largely unexplored. To date, four different PARs have been identified: PAR1, PAR2, PAR3, and PAR4. 8,9 -13 PAR1 originally was discovered on platelets and serves as the prototype for this specialized class of proteolytically activ...

show abstract

Thrombin induced secretion of macrophage migration inhibitory factor (MIF) and its effect on nuclear signaling in endothelium

Cited by 25 publications

References 46 publications

Macrophage Migration Inhibitory Factor Increases Leukocyte–Endothelial Interactions in Human Endothelial Cells via Promotion of Expression of Adhesion Molecules

Macrophage Migration Inhibitory Factor Increases Leukocyte–Endothelial Interactions in Human Endothelial Cells via Promotion of Expression of Adhesion Molecules

Coagulation and innate immune responses: can we view them separately?

Targeting Protease-Activated Receptor-1 with Cell-Penetrating Pepducins in Lung Cancer

Contact Info

Product

Resources

About