A Lymphocyte Serine Protease Granzyme A Causes Detachment of a Small-Intestinal Epithelial Cell Line (IEC-6)

Hirayasu, Hirofumi; Yoshikawa, Yumiko; Tsuzuki, Satoshi; Fushiki, Tohru

doi:10.1271/bbb.80140

Cited by 21 publications

(20 citation statements)

References 21 publications

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“…We could not detect Perf expression by eosinophils. Recent results, however, suggest that, on one hand, Perf is not necessary for the entry of granzyme, raising doubt about the molecular mechanisms involved (41), and, on the other hand, that GzmA might be involved in vivo in enterocyte exfoliation through cleavage of extracellular matrix components (42,43), stressing its putative toxic properties toward intestinal tissue. Purified GzmA induces detachment of the intestinal epithelial cell line or to induce rapid caspase-independent apoptosis of target cells in vitro (30,44).…”

Section: Discussionmentioning

confidence: 99%

Human Eosinophils Exert TNF-α and Granzyme A-Mediated Tumoricidal Activity toward Colon Carcinoma Cells

Legrand

Driss

Delbeke

et al. 2010

The Journal of Immunology

144

135

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Peripheral blood and tissue eosinophilia is a prominent feature in allergic diseases and helminth infections. In cancer patients, tumor-associated tissue eosinophilia is frequently observed. Tumor-associated tissue eosinophilia can be associated with a favorable prognosis, notably in colorectal carcinoma. However, underlying mechanisms of eosinophil contribution to antitumor responses are poorly understood. We have in this study investigated the direct interactions of human eosinophils with Colo-205, a colorectal carcinoma cell line, and show that eosinophils induce apoptosis and directly kill tumor cells. Using blocking Abs, we found that CD11a/CD18 complex is involved in the tumoricidal activity. Coculture of eosinophils with Colo-205 led to the release of eosinophil cationic protein and eosinophil-derived neurotoxin as well as TNF-α secretion. Moreover, eosinophils expressed granzyme A, which was released upon interaction with Colo-205, whereas cytotoxicity was partially inhibited by FUT-175, an inhibitor of trypsin-like enzymatic activity. Our data present the first demonstration, to our knowledge, that granzyme A is a cytotoxic mediator of the eosinophil protein arsenal, exerting eosinophil tumoricidal activity toward Colo-205, and provide mechanistic evidence for innate responses of eosinophil against tumor cells.

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Section: Discussionmentioning

confidence: 99%

Human Eosinophils Exert TNF-α and Granzyme A-Mediated Tumoricidal Activity toward Colon Carcinoma Cells

Legrand

Driss

Delbeke

et al. 2010

The Journal of Immunology

144

135

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“…26,75,76 Extracellular substrates for granzyme A are only beginning to emerge (Table 1); however, it is possible that proteolysis of cell surface proteins by circulating granzyme A may mediate some of the damage seen in proinflammatory disease states associated with this enzyme. 77 Although granzyme A was observed to promote cytokine release from monocytes and to cleave and possibly activate the proinflammtory cytokine IL-1b over 20 years ago, a causal link between high levels of circulating granzyme A and the propagation of proinflammatory conditions was not fully appreciated until recently. 78,79 In addition to the previously described role in monocyte activation, Metkar et al 12 have shown that granzyme A, whether purified or supplied by CTL, can promote the release of IL-1b from primary mouse macrophages.…”

Section: Extracellular Role Of Granzymes In Immune Reactionsmentioning

confidence: 99%

Granzymes in cancer and immunity

2010

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“…not significant Cytotechnology (2014) 66:357-363 361 of death in SIECs of mice (Fouquet et al 2004). We also found (i) that IEC-6 cells detached as aggregates by treatment with a serine proteases granzyme A and displayed no characteristics of apoptosis (Hirayasu et al 2008) and (ii) that after detachment by treatment with r-MatCD, single IEC-6 cells were mostly positive for annexin-V staining, whereas the ones maintaining cellcell contact (i.e., small cell aggregates) were not (Mochida et al 2010). Judging from the spindle-like morphology, r-MatCD-treated IEC-6 cells on fibronectin might undergo loss of cell-cell adhesions.…”

Section: Resultsmentioning

confidence: 67%

A recombinant matriptase causes an increase in caspase-3 activity in a small-intestinal epithelial IEC-6 line cultured on fibronectin-coated plates

et al. 2013

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Matriptase is an epithelial-derived type-II transmembrane serine protease. This protease is expressed prominently in the villus tip of smallintestinal epithelia at which senescent cells undergo shedding and/or apoptosis. The basement membrane of epithelial cells, including small-intestinal epithelial cells, contains extracellular matrix (ECM) proteins such as fibronectin and laminin. We found previously that high concentrations of a recombinant matriptase catalytic domain (r-MatCD) (e.g. 1 lM) caused an increased detachment of and increases in the activity of apoptotic effector caspase-3 in a rat small-intestinal epithelial IEC-6 line cultured on laminin-coated plates and proposed that at sites with its high level of expression, matriptase contributes to promoting shedding and/or detachment-induced death of epithelial cells through a mechanism mediating loss of cell-ECM adhesion. In this study, we found that even without increasing cell detachment, a high concentration of r-MatCD causes an increase in caspase-3 activity in IEC-6 cells cultured on fibronectin-coated plates, suggesting that the recombinant matriptase can cause apoptosis by a mechanism unrelated to cell detachment. Also, r-MatCD-treated IEC-6 cells on fibronectin were found to display spindle-like morphological changes. We suggest that r-MatCD causes apoptosis of IEC-6 on fibronectin by a mechanism involving the disruption of cell integrity.

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A Lymphocyte Serine Protease Granzyme A Causes Detachment of a Small-Intestinal Epithelial Cell Line (IEC-6)

Cited by 21 publications

References 21 publications

Human Eosinophils Exert TNF-α and Granzyme A-Mediated Tumoricidal Activity toward Colon Carcinoma Cells

Human Eosinophils Exert TNF-α and Granzyme A-Mediated Tumoricidal Activity toward Colon Carcinoma Cells

Granzymes in cancer and immunity

A recombinant matriptase causes an increase in caspase-3 activity in a small-intestinal epithelial IEC-6 line cultured on fibronectin-coated plates

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