Functional effects of the inhibition of the cysteine protease activity of the major house dust mite allergen Der p 1 by a novel peptide‐based inhibitor

John, Richard R.; Rusznák, C.; Ramjee, Manoj K.; Lamont, Alan; Abrahamson, Magnus; Hewitt, Ellen

doi:10.1046/j.1365-2222.2000.00840.x

Cited by 38 publications

(31 citation statements)

References 39 publications

(61 reference statements)

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“…Our findings demonstrate that accumulated CRTH2 + CD4 + T H 2 memory cells are closely associated with DC-LAMP + DCs within dermis of lesional skin of AD, but not T H 1-mediated inflammatory skin diseases, suggesting that TSLP-DCs may interact with CRTH2 + CD4 + T H 2 effector memory cells and induce their further T H 2 polarization at the inflammatory sites, thereby contributing to the maintenance and relapse of T H 2-mediated allergic diseases. These in vivo observations were further substantiated by the findings that signals from TSLP-DCs are the most effective on upregulation of genes involved in T H 2 polarization, such as CRTH2, GATA-3, c-MAF, and IL17RB (Fort et al, 2001;Matsuoka et al, 2000), as well as genes encoding the proteins that are found in epithelial cells, eosinophils, basophils, or antigen-presenting cells during allergic inflammation, including the T H 2-attracting chemokine TARC, cystatin A (John et al, 2000), CharcotLeydon crystal protein (Golightly et al, 1992;Ackerman et al, 1993), and prostaglandin D2 synthase. Our findings broaden the understanding of heterogeneous T H 2 cells that are not only the principal producers of T H 2 cytokines but also capable of producing other effective molecules to trigger allergic inflammation.…”

Section: Discussionmentioning

confidence: 76%

“…By contrast, TSLP-DCs do not induce the expression of genes encoding chemokines lymphotactin, MIP-1a, and MIP-1b, which are produced during T H 1-polarized inflammation (Ritz et al, 2004;Muller et al, 2003), and IFN-g, IL-18Rap, CCR5, and CD70, which are expressed by T H 1 or T EM cells. Interestingly, only TSLP-DCs induced CRTH2 + CD4 + T H 2 memory cells to express genes encoding cystatin A, Charcot-Leydon crystal protein, and prostaglandin D2 synthase, which are known to be selectively expressed by eosinophils and basophils (Golightly et al, 1992;Ackerman et al, 1993) and critical for allergic inflammation (John et al, 2000;Matsuoka et al, 2000), as well as chemokine TARC known to recruit T H 2 cells (Ritz et al, 2004) ( Figure 3B). These results suggest that TSLP-DCs not only maintain the central memory phenotype but also further strengthen the ''T H 2'' properties of CRTH2 + CD4 + T H 2 memory cells.…”

Section: T H 2 Progression Of Crth2 + Cd4 + T H 2 Memory Cells Inducementioning

confidence: 96%

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Maintenance and Polarization of Human TH2 Central Memory T Cells by Thymic Stromal Lymphopoietin-Activated Dendritic Cells

Wang¹,

Ito²,

Wang³

et al. 2006

Immunity

294

291

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The identity of TH2 memory cells and the mechanism regulating their maintenance during allergic inflammation remain elusive. We report that circulated human CD4+ T cells expressing the prostaglandin D2 receptor (CRTH2) are TH2 central memory T cells, characterized by their phenotype, TH2 cytokine production, gene-expression profile, and the ability to respond to allergens. Only dendritic cells (DCs) activated by thymic stromal lymphopoietin (TSLP) can induce a robust expansion of CRTH2+CD4+ TH2 memory cells, while maintaining their central memory phenotype and TH2 commitments. CRTH2+CD4+ TH2 memory cells activated by TSLP-DCs undergo further TH2 polarization and express cystatin A, Charcot-Leydon crystal protein, and prostaglandin D2 synthase, implying their broader roles in allergic inflammation. Infiltrated CRTH2+CD4+ TH2 effector memory T cells in skin lesion of atopic dermatitis were associated with activated DCs, suggesting that TSLP-DCs play important roles not only in TH2 priming, but also in the maintenance and further polarization of TH2 central memory cells in allergic diseases.

show abstract

Section: Discussionmentioning

confidence: 76%

Section: T H 2 Progression Of Crth2 + Cd4 + T H 2 Memory Cells Inducementioning

confidence: 96%

Maintenance and Polarization of Human TH2 Central Memory T Cells by Thymic Stromal Lymphopoietin-Activated Dendritic Cells

Wang¹,

Ito²,

Wang³

et al. 2006

Immunity

294

291

View full text Add to dashboard Cite

show abstract

“…Actually, it has been reported that a peptide-based inhibitor, PTL11028, showed inhibitory effects for the catalytic activities of group I mite allergens and improved airway hyperreactivity, inflammation, and systemic sensitization induced by Der p 1 in rats (40,41). Structural analyses of the interaction between SCCA/Der p 1 would give us a hint as to how to develop a novel low molecular weight compound to block the catalytic activity of group I mite allergens.…”

Section: Discussionmentioning

confidence: 99%

The Squamous Cell Carcinoma Antigen 2 Inhibits the Cysteine Proteinase Activity of a Major Mite Allergen, Der p 1

Sakata¹,

Arima²,

Takai

et al. 2004

Journal of Biological Chemistry

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The squamous cell carcinoma antigens 1 (SCCA1) and SCCA2 belong to the ovalbumin-serpin family. Although SCCA1 and SCCA2 are closely homologous, these two molecules have distinct properties; SCCA1 inhibits cysteine proteinases such as cathepsin K, L, and S, whereas SCCA2 inhibits serine proteinases such as cathepsin G and human mast cell chymase. Although several intrinsic target proteinases for SCCA1 and SCCA2 have been found, the biological roles of SCCA1 and SCCA2 remain unknown. A mite allergen, Der p 1, is one of the most immunodominant allergens and also acts as a cysteine proteinase probably involved in the pathogenesis of allergic diseases. We have recently shown that both SCCA1 and SCCA2 are induced by two related Th2-type cytokines, IL-4 and IL-13, in bronchial epithelial cells and that SCCA expression is augmented in bronchial asthma patients. In this study, we explored the possibility that SCCA proteins target Der p 1, and it turned out that SCCA2, but not SCCA1, inhibited the catalytic activities of Der p 1. We furthermore analyzed the inhibitory mechanism of SCCA2 on Der p 1. SCCA2 contributed the suicide substrate-like mechanism without formation of a covalent complex, causing irreversible impairment of the catalytic activity of Der p 1, as SCCA1 does on papain. In addition, resistance to cleavage by Der p 1 also contributed to the inhibitory mechanism of SCCA2. These results suggest that SCCA2 acts as a crossclass serpin targeting an extrinsic cysteine proteinase derived from house dust mites and that it may have a protective role against biological reactions caused by mites.

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“…Given their role in immune responses, it is perhaps not surprising that cystatins (e.g., cat Fel d3; Ichikawa et al, 2001), CPs (e.g., dust mite der P1; John et al, 2000, and references therein), and papain-related enzymes (Mansfield et al, 1985) can be potent allergens. Analysis of the above data argues for an intimate relationship between cystatins and regulation of the immune system.…”

Section: (3) Immunomodulationmentioning

confidence: 99%

Salivary (SD-Type)Cystatins:OverOneBillionYears in theMaking—But toWhatPurpose?

Dickinson

2002

Critical Reviews in Oral Biology & Medicine

103

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The cystatin superfamily is comprised of a large group of ancestrally related proteins, most of which are potent inhibitors of cysteine peptidases (CPs). Human saliva contains relatively abundant proteins that are related ancestrally in sequence to the cystatin superfamily. These proteins are now commonly referred to as 'salivary cystatins', although this is something of a misnomer (see below). It has been several years since the publication of the last comprehensive reviews that focused on the salivary cystatins (Bobek and Levine, 1992;Henskens et al., 1996c). Since then, significant advances have been made regarding the gene organization, protein structure, and properties of human and rat proteins. Therefore, a major purpose of this article is to review this recent work. What is the function of the 'salivary cystatins'? Despite a great deal of research effort, we still do not have a definitive answer to this question. A major impediment is the lack of a disease to associate with a specific defect in a gene: Functionality must be inferred from circumstantial evidence. A central premise of this review is that clues to 'salivary cystatin' function are contained within their phylogenetic history, and that by looking at established or likely functions of their 'siblings' and 'cousins', one can assess the likelihood of this function(s) continuing into the 'salivary cystatins'. A comprehensive review of the large cystatin superfamily is beyond the scope of a single article. This review will aim to outline the main branches of the superfamily and the common elements of their structure and function, but will pay closest attention to the nearest relatives of the 'salivary cystatins'.(1) BACKGROUND Scission of peptide bonds is an essential reaction in living cells, and there is a considerable number of peptidases that catalyze this reaction with various degrees of specificity. CPs use a cysteine residue in the active site as the nucleophile in the reaction (see Dickinson, 2002, and references therein). Release of proteolytic enzymes outside of their normal compartment has the potential to cause serious degradation and pathology-an effect taken advantage of by pathogenic organisms from a wide range of phyla. Therefore, control of proteolytic enzyme activity is mandatory. Building upon a very early report (see Barrett et al., 1986, for a review of this earlier literature) of a bovine trypsin inhibitor in chicken egg white, a search for egg white inhibitors of plant proteinases (the CPs ficin and papain) identified a relatively small (12.7 kDa) protein that was a potent inhibitor (Ki = 10 nM). The term cystatin was coined for this protein, which was shown also to inhibit mammalian CPs of the papain superfamily, including cathepsins B, C, H, and L. Cystatins form 1:1 reversible complexes with CPs, in competition with the substrate, but in some cases the binding is so tight as to be physiologically irreversible. (2) THE CYSTATIN SUPERFAMILYExamination of mammalian tissues and serum revealed several CP inhibitors ranging in si...

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Functional effects of the inhibition of the cysteine protease activity of the major house dust mite allergen Der p 1 by a novel peptide‐based inhibitor

Cited by 38 publications

References 39 publications

Maintenance and Polarization of Human TH2 Central Memory T Cells by Thymic Stromal Lymphopoietin-Activated Dendritic Cells

Maintenance and Polarization of Human TH2 Central Memory T Cells by Thymic Stromal Lymphopoietin-Activated Dendritic Cells

The Squamous Cell Carcinoma Antigen 2 Inhibits the Cysteine Proteinase Activity of a Major Mite Allergen, Der p 1

Salivary (SD-Type)Cystatins:OverOneBillionYears in theMaking—But toWhatPurpose?

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