PAR<sub>2</sub>expression in peripheral blood monocytes of patients with rheumatoid arthritis

Crilly, Anne; Burns, Elizabeth M.; Nickdel, Mohammad B.; Lockhart, John C.; Perry, Martin E; Ferrell, P W; Baxter, Derek; Dale, James; Dunning, Lynette; Wilson, Hilary; Nijjar, Jagtar Singh; Gracie, J. Alastair; Ferrell, William R.; McInnes, Iain B.

doi:10.1136/annrheumdis-2011-200703

Cited by 27 publications

(25 citation statements)

References 26 publications

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“…In contrast, Crilly et al . found PAR‐2 expression on monocytes in their study . However, this PAR‐2 expression was very limited in healthy humans with a median expression of 0.06%.…”

Section: Discussionmentioning

confidence: 76%

Stimulation of Naïve Monocytes and PBMCs with Coagulation Proteases Results in Thrombin‐Mediated and PAR‐1‐Dependent Cytokine Release and Cell Proliferation in PBMCs Only

et al. 2013

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Protease-activated receptors (PARs) are stimulated by proteolytic cleavage of their extracellular domain. Coagulation proteases, such as FVIIa, the binary TFFVIIa complex, free FXa, the ternary TF-FVIIa-FXa complex and thrombin, are able to stimulate PARs. Whereas the role of PARs on platelets is well known, their function in na€ ıve monocytes and peripheral blood mononuclear cells (PBMCs) is largely unknown. This is of interest because PAR-mediated interactions of coagulation proteases with monocytes and PBMCs in diseases with an increased activation of coagulation may promote inflammation. To evaluate PAR-mediated inflammatory reactions in na€ ıve monocytes and PBMCs stimulated with coagulation proteases. For this, PAR expression at protein and RNA level on na€ ıve monocytes and PBMCs was evaluated with flow cytometry and RT-PCR. In addition, cytokine release (IL-1b, IL-6, IL-8, IL-10, TNF-a) in stimulated na€ ıve and PBMC cell cultures was determined. In this study, it is demonstrated that na€ ıve monocytes express all four PARs at the mRNA level, and PAR-1, -3 and -4 at the protein level. Stimulation of na€ ıve monocytes with coagulation proteases did not result in alterations in PAR expression or in the induction of inflammation involved cytokines like interleukin-1b (IL-1b), interleukin-6 (IL-6), interleukin-8, interleukin-10 or tumour necrosis factor-a. In contrast, stimulation of PBMCs with coagulation proteases resulted in thrombin-mediated induction of IL-1b and IL-6 cytokine production and PBMC cell proliferation in a PAR-1-dependent manner. These data demonstrate that na€ ıve monocytes are not triggered by coagulation proteases, whereas thrombin is able to elicit pro-inflammatory events in a PAR-1-dependent manner in PBMCs.

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“…In contrast, Crilly et al . found PAR‐2 expression on monocytes in their study . However, this PAR‐2 expression was very limited in healthy humans with a median expression of 0.06%.…”

Section: Discussionmentioning

confidence: 76%

Stimulation of Naïve Monocytes and PBMCs with Coagulation Proteases Results in Thrombin‐Mediated and PAR‐1‐Dependent Cytokine Release and Cell Proliferation in PBMCs Only

et al. 2013

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“…18 Many of these, in turn, have been implicated in the pathology of chronic inflammatory diseases, such as RA. 19 In addition, we have shown recently that RA patients having a disease flare have increased levels of PAR-2 expression on their PBMC than individuals with stable disease, 20 supporting an inflammatory role for this molecule in the disease.…”

Section: Introductionmentioning

confidence: 98%

Proteinase-activated receptor-2 modulates human macrophage differentiation and effector function

et al. 2013

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Proteinase-activated receptor-2 (PAR-2) was shown to influence immune regulation; however, its role in human macrophage subset development and function has not been addressed. Here, PAR-2 expression and activation was investigated on granulocyte macrophage (GM)-CSF(M1) and macrophage (M)-CSF(M2) macrophages. In both macrophages, the PAR-2-activating peptide, SLIGKV, increased PAR-2 expression and regulated TNF-α and IL-10 secretion in a manner similar to LPS. In addition, HLA-DR on M1 cells also increased. Monocytes matured to an M1 phenotype in the presence of SLIGKV had reduced cell area, and released less TNF-α after LPS challenge compared with vehicle (P < 0.05, n = 3). Cells matured to an M2 phenotype with SLIGKV also had a reduced cell area and made significantly more TNF-α after LPS exposure compared to vehicle (P < 0.05, n = 3) with reduced IL-10 secretion (P < 0.05, n = 3). Thus, PAR-2 activation on macrophage subsets regulates HLA-DR and PAR-2 surface expression, and drives cytokine production. In contrast, PAR-2 activation during M1 or M2 maturation induces altered cell morphology and skewing of phenotype, as evidenced by cytokine secretion. These data suggest a complex role for PAR-2 in macrophage biology and may have implications for macrophage-driven disease in which proteinase-rich environments can influence the immune process directly.

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“…Our study demonstrates that blocking of PAR1–4 resulted in reduction in the severity of synovitis and cartilage damage following a joint bleed in haemophilic mice. Similar protective effects on the severity of arthritis are found in studies using PAR1 and PAR2‐deficient mice . In this proof of concept study we choose to silence all four PARs as it is known that the affinity of plasmin is practically similar for all PARs.…”

Section: Discussionmentioning

confidence: 78%

“…# P < 0.05, loglinear analysis and Pearson chi-square were used for comparison between the left unaffected and right blood-exposed knee joint. arthritis are found in studies using PAR1 and PAR2deficient mice [34][35][36]. In this proof of concept study we choose to silence all four PARs as it is known that the affinity of plasmin is practically similar for all PARs.…”

Section: Discussionmentioning

confidence: 99%

Silencing of protease‐activated receptors attenuates synovitis and cartilage damage following a joint bleed in haemophilic mice

et al. 2015

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PAR₂expression in peripheral blood monocytes of patients with rheumatoid arthritis

Cited by 27 publications

References 26 publications

Stimulation of Naïve Monocytes and PBMCs with Coagulation Proteases Results in Thrombin‐Mediated and PAR‐1‐Dependent Cytokine Release and Cell Proliferation in PBMCs Only

Stimulation of Naïve Monocytes and PBMCs with Coagulation Proteases Results in Thrombin‐Mediated and PAR‐1‐Dependent Cytokine Release and Cell Proliferation in PBMCs Only

Proteinase-activated receptor-2 modulates human macrophage differentiation and effector function

Silencing of protease‐activated receptors attenuates synovitis and cartilage damage following a joint bleed in haemophilic mice

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PAR2expression in peripheral blood monocytes of patients with rheumatoid arthritis

Cited by 27 publications

References 26 publications

Stimulation of Naïve Monocytes and PBMCs with Coagulation Proteases Results in Thrombin‐Mediated and PAR‐1‐Dependent Cytokine Release and Cell Proliferation in PBMCs Only

Stimulation of Naïve Monocytes and PBMCs with Coagulation Proteases Results in Thrombin‐Mediated and PAR‐1‐Dependent Cytokine Release and Cell Proliferation in PBMCs Only

Proteinase-activated receptor-2 modulates human macrophage differentiation and effector function

Silencing of protease‐activated receptors attenuates synovitis and cartilage damage following a joint bleed in haemophilic mice

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PAR₂expression in peripheral blood monocytes of patients with rheumatoid arthritis