Mast Cell Chymase Decreases the Barrier Function and Inhibits the Migration of Corneal Epithelial Cells

Ebihara, Nobuyuki; Funaki, Toshinari; Murakami, Akira; Takai, Shinji; Miyazaki, Mizuo

doi:10.1080/02713680500346625

Cited by 27 publications

(19 citation statements)

References 60 publications

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“…Mast cell chymase has been shown to be apoptotic in leukemic T cells by inducing DNA fragmentation [32] as well as in vascular smooth muscle cells [33] and in keratinocytes [19]. In addition, chymase inhibited migration of corneal epithelial cells [34]. In our specimens, the lack of microsatellites might be explained by increased apoptosis and reduced migration of melanoma cells in the presence of chymase in the peritumoral stroma.…”

Section: Discussionmentioning

confidence: 78%

Low numbers of tryptase+ and chymase+ mast cells associated with reduced survival and advanced tumor stage in melanoma

Siiskonen

Poukka

Bykachev³

et al. 2015

Melanoma Research

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The role of mast cells in cutaneous melanoma remains unclear. Tryptase and chymase are serine proteinases and major proteins in mast cell secretory granules. Therefore, this study aimed to investigate the presence of tryptase and chymase mast cells in benign and malignant cutaneous melanocytic lesions and in lymph node metastases of melanomas. The presence of positively stained mast cells was correlated with clinicopathological characteristics in invasive melanomas. Paraffin-embedded sections of 28 benign (13 intradermal, 10 compound, and five junctional nevi) and 26 dysplastic nevi, 15 in-situ melanomas, 36 superficially (pT1, Breslow's thickness<1 mm), and 49 deeply (pT4, Breslow's thickness>4 mm) invasive melanomas and 30 lymph node metastases were immunohistochemically stained for mast cell tryptase and chymase, and immunopositive cells were counted using the hotspot counting method. The mean count of tryptase and chymase mast cells was lower in invasive melanomas compared with in-situ melanomas and dysplastic and benign nevi. In deeply invasive melanomas, the difference was statistically significant compared with dysplastic nevi (P=0.003 for tryptase and P=0.009 for chymase) and in-situ melanomas (0.043 for tryptase). Low numbers of tryptase mast cells were associated with poor overall survival (P=0.031) in deeply invasive melanomas and with a more advanced stage (T1b, P=0.008) in superficially invasive melanomas. Low numbers of chymase mast cells were associated with microsatellites (P=0.017) in deeply invasive melanomas. The results suggest that these serine proteinases of mast cells may be protective in the pathogenesis of melanoma.

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Section: Discussionmentioning

confidence: 78%

Low numbers of tryptase+ and chymase+ mast cells associated with reduced survival and advanced tumor stage in melanoma

Siiskonen

Poukka

Bykachev³

et al. 2015

Melanoma Research

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“…Although the underlying mechanism has not been fully established, it has been suggested that mMCP-1 may promote inflammation by cleaving cell-cell contact proteins, such as occludin and ZO-1. 44,55,56 In line with such a notion, infusion of rats with rMCP-2, that is, a rat homolog of mMCP-1, causes increased epithelial permeability. 57 …”

Section: Parasite Infectionmentioning

confidence: 69%

“…44,55,56 Further, MC proteases may regulate the local gene expression pattern, as exemplified by the ability of tryptase to induce chemokine secretion. 34 It is also well known that tryptase can cleave and thereby activate protease-activated receptor 2, 85-87 a notion that is also supported by in vivo evidence.…”

Section: Effects On Cell Surface Proteinsmentioning

confidence: 99%

Mast cell proteases: multifaceted regulators of inflammatory disease

Pejler

Rönnberg

Waern

et al. 2010

Blood

334

296

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IntroductionMast cells (MCs) are still mainly known for their harmful effects in connection with allergic reactions. However, this simplistic view is currently being extensively modified, and it is becoming more and more established that MCs have a complex array of functions and can contribute to a number of additional disorders. 1 In addition to being detrimental, MCs also carry out a number of beneficial functions, most notably in connection with innate immune responses toward various pathogens. 2 Moreover, recent studies indicate that MCs can play important roles in down-regulating adaptive immune responses. 3,4 As a consequence of this progress, MCs are gaining a massively increased interest worldwide, and much effort is invested into investigations of the mechanisms by which MCs contribute to different disorders.A striking morphologic feature of MCs is their abundance of electron-dense secretory granules, which contain large amounts of preformed compounds commonly referred to as "MC mediators." These include biogenic amines (histamine and serotonin), certain preformed cytokines (most notably tumor necrosis factor), serglycin proteoglycans, various lysosomal enzymes, and a number of MC-specific proteases of chymase, tryptase, or carboxypeptidase A (MC-CPA) type. [5][6][7][8] When MCs are induced to undergo degranulation, for example, through engagement of Fc⑀RI-bound IgE by polyvalent antigen, these mediators are thus released. 9 The MC proteases are expressed at exceptionally high levels, with mRNA levels approaching and even exceeding those of classic housekeeping genes, 10 and they are stored in remarkably high amounts. Indeed, it has been calculated that MC proteases may account for more than 25% of the total MC protein. 11,12 Importantly, in contrast to, for example, the pancreatic digestive proteases, the MC proteases are stored in fully active form; and when MCs undergo degranulation, large amounts of enzymatically active proteases are thus released into the extracellular space and probably have a profound impact on any condition in which MC degranulation occurs (Figure 1). Indeed, a plethora of potential functions of the MC proteases have previously been outlined, based on various approaches. 6 However, it is not until relatively recently that the in vivo functions of these enzymes have started to become unraveled through experimental approaches involving MC proteasedeficient mice. In this review, we summarize these findings and discuss their implications. Substrate specificity, distribution, and storageThe term "MC proteases" usually refers to the proteases that are expressed specifically by MCs and are stored in their secretory granules, that is, chymases, tryptases, and MC-CPA. However, it should be pointed out that MCs express a number of additional, non-MC-specific, proteases, such as lysosomal cathepsins, granzymes, neurolysin, and, possibly, cathepsin G. 6 Recently, the strictly MC-specific expression of the chymases has been used to generate mouse strains in which the Cre recombinase is expre...

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“…Consequently, mast cell chymase may affect barrier function through effects on any of these systems. Chymase directly alters corneal epithelial barrier function through proteolytic cleavage of fibronectin and the TJ protein occludin (30). Alternatively, mast cell/chymase may regulate epithelial barrier function indirectly via interactions with the enteric nervous system (ENS).…”

Section: Mcpt7 Andmentioning

confidence: 99%

Mast cells regulate homeostatic intestinal epithelial migration and barrier function by a chymase/Mcpt4-dependent mechanism

Groschwitz¹,

Ahrens²,

Osterfeld³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

162

140

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Mast Cell Chymase Decreases the Barrier Function and Inhibits the Migration of Corneal Epithelial Cells

Abstract: Human chymase causes the proteolysis of occludin and fibronectin, resulting in a decrease of barrier function and inhibition of the migration of corneal epithelial cells.

Cited by 27 publications

References 60 publications

Low numbers of tryptase+ and chymase+ mast cells associated with reduced survival and advanced tumor stage in melanoma

Low numbers of tryptase+ and chymase+ mast cells associated with reduced survival and advanced tumor stage in melanoma

Mast cell proteases: multifaceted regulators of inflammatory disease

Mast cells regulate homeostatic intestinal epithelial migration and barrier function by a chymase/Mcpt4-dependent mechanism

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