The Serine Protease Inhibitor, 4-(2-aminoethyl) Benzene Sulfonyl Fluoride Hydrochloride, Reduces Allergic Inflammation in a House Dust Mite Allergic Rhinitis Mouse Model

Kim, Boo‐Young; Park, Hyang Rim; Shin, Ji-Hyeon; Kim, Sung Won; Cho, Jin Hee; Park, Yong Jin; Kim, Soo Whan

doi:10.4168/aair.2014.6.6.558

Cited by 9 publications

(9 citation statements)

References 34 publications

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“…Furthermore, such increase in IL-17 but decrease in IL-22 coincided with a significant increase in the percentage of CD4 + /CD25 + /Foxp3 + T-reg cell population in spleens of HDM-exposed animals ( Figure 6 F). HDM exposure did not increase the percentage of T-reg cells in spleens of WT mice ( Figure 6 F), which is consistent with the report by Kim et al [ 24 ]. The T-reg cell population was also increased in PARP-1 −/− mice without any HDM exposure.…”

Section: Clinical Perspectivessupporting

confidence: 92%

PARP is activated in human asthma and its inhibition by olaparib blocks house dust mite-induced disease in mice

et al. 2015

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Section: Clinical Perspectivessupporting

confidence: 92%

PARP is activated in human asthma and its inhibition by olaparib blocks house dust mite-induced disease in mice

et al. 2015

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“…In addition, the corresponding profiles made possible the identification of a panel of potential novel substrates for these protease allergens. Our results could pave the way to a better understanding of the role of these proteases in the mechanism of the HDM allergic response but also to the design of specific protease inhibitors for future anti-allergic treatments as suggested by previous promising studies [ 35 , 58 ].…”

Section: Discussionmentioning

confidence: 70%

Profiling the Extended Cleavage Specificity of the House Dust Mite Protease Allergens Der p 1, Der p 3 and Der p 6 for the Prediction of New Cell Surface Protein Substrates

Jacquet

Campisi

Szpakowska

et al. 2017

IJMS

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House dust mite (HDM) protease allergens, through cleavages of critical surface proteins, drastically influence the initiation of the Th2 type immune responses. However, few human protein substrates for HDM proteases have been identified so far, mainly by applying time-consuming target-specific individual studies. Therefore, the identification of substrate repertoires for HDM proteases would represent an unprecedented key step toward a better understanding of the mechanism of HDM allergic response. In this study, phage display screenings using totally or partially randomized nonameric peptide substrate libraries were performed to characterize the extended substrate specificities (P5–P4′) of the HDM proteases Der p 1, Der p 3 and Der p 6. The bioinformatics interface PoPS (Prediction of Protease Specificity) was then applied to define the proteolytic specificity profile of each protease and to predict new protein substrates within the human cell surface proteome, with a special focus on immune receptors. Specificity profiling showed that the nature of residues in P1 but also downstream the cleavage sites (P′ positions) are important for effective cleavages by all three HDM proteases. Strikingly, Der p 1 and Der p 3 display partially overlapping specificities. Analysis with PoPS interface predicted 50 new targets for the HDM proteases, including 21 cell surface receptors whose extracellular domains are potentially cleaved by Der p 1, Der p 3 and/or Der p 6. Twelve protein substrate candidates were confirmed by phage ELISA (enzyme linked immunosorbent assay). This extensive study of the natural protein substrate specificities of the HDM protease allergens unveils new cell surface target receptors for a better understanding on the role of these proteases in the HDM allergic response and paves the way for the design of specific protease inhibitors for future anti-allergic treatments.

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“…Regulatory IL-10 cytokine down-modulates both type 1 and type 2 cytokines and induces anergy of effector T cells [ 47 ]. Effective treatment with AEBSF [ 27 , 48 ] or nafamostat mesilate [ 46 ] on experimental asthma induced the production of IL-10. More recently, Kim et al .…”

Section: Discussionmentioning

confidence: 99%

“…More recently, Kim et al . showed that, in addition to increased levels of IL-10, treatment of allergic mice with AEBSF induce CD4 + CD25 + FoxP3 + T cells [ 48 ]. Our results do not support a role for this cytokine in this protocol since IL-10 was also diminished in both treated groups.…”

Section: Discussionmentioning

confidence: 99%

“…The fact that targeting proteolytic activity by synthetic inhibitors such as AEBSF [ 27 , 48 ] or nafamostat mesilate [ 46 ] reduces allergic airway inflammation in a mouse model suggests that inhibition of at least some serine proteases should be sufficient for the decrease of the severity of the disease. However, the effect of rTgPI-1 on allergic inflammation could be given not only by blocking the activity of proteases but also by still unknown immunomodulatory properties independent of its anti-protease activity.…”

Section: Discussionmentioning

confidence: 99%

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Toxoplasma gondii serine-protease inhibitor-1: A new adjuvant candidate for asthma therapy

et al. 2017

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Serine-proteases are important players in the pathogenesis of asthma, promoting inflammation and tissue remodeling. It’s also known that many serine protease inhibitors display immunomodulatory properties. TgPI-1 is a Toxoplasma gondii protein that exhibits broad spectrum inhibitory activity against serine proteases. In view of the increased prevalence of atopic disorders and the need to develop new treatment strategies we sought to investigate the potential of TgPI-1 for treating respiratory allergies. For this purpose, we developed a therapeutic experimental model. BALB/c mice were rendered allergic by intraperitoneal ovalbumin-alum sensitization and airway-challenged. Once the asthmatic phenotype was achieved, mice were intranasally treated with rTgPI-1 alone or with a mixture of rTgPI-1 and ovalbumin (OVA). A week later mice were given a secondary aerosol challenge. Treatment with rTgPI-1 alone or co-administered with OVA diminished bronchoalveolar eosinophilia, mucus production and peribronchial lung infiltration. This effect was accompanied by a lung resistance reduction of 26.3% and 50.3% respectively. Both treatments resulted in the production of lower levels of IL-4, IL-5, IFN-γ and regulatory IL-10 by thoracic lymph node cells stimulated with OVA. Interestingly, significant decreases in OVA specific IgE and T cell proliferation, and increases in FoxP3+ T cells at local and systemic levels were only detected when the inhibitor was administered along with OVA. These results show that both rTgPI-1 treatments reduced asthma hallmarks. However, co-administration of the inhibitor with the allergen was more effective. Hence, rTgPI-1 emerges as a novel adjuvant candidate for asthma treatment.

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The Serine Protease Inhibitor, 4-(2-aminoethyl) Benzene Sulfonyl Fluoride Hydrochloride, Reduces Allergic Inflammation in a House Dust Mite Allergic Rhinitis Mouse Model

Cited by 9 publications

References 34 publications

PARP is activated in human asthma and its inhibition by olaparib blocks house dust mite-induced disease in mice

PARP is activated in human asthma and its inhibition by olaparib blocks house dust mite-induced disease in mice

Profiling the Extended Cleavage Specificity of the House Dust Mite Protease Allergens Der p 1, Der p 3 and Der p 6 for the Prediction of New Cell Surface Protein Substrates

Toxoplasma gondii serine-protease inhibitor-1: A new adjuvant candidate for asthma therapy

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