Cathepsin C Regulates Cytokine-Induced Apoptosis in β-Cell Model Systems

Emerging evidence suggests that several of the lysosomal cathepsin proteases are genetically associated with type 1 diabetes (T1D) and participate in immune-mediated destruction of the pancreatic β cells. We previously reported that the T1D candidate gene cathepsin H is downregulated by pro-inflamma...

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Autores principales:	Tina Fløyel, Caroline Frørup, Joachim Størling, Flemming Pociot
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	type 1 diabetes lysosomal proteases β-cell death CTSC MAPK CXCL10 Genetics QH426-470
Acceso en línea:	https://doaj.org/article/a22d1491e7304840bd0de14a3c261627
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spelling	oai:doaj.org-article:a22d1491e7304840bd0de14a3c2616272021-11-25T17:40:55ZCathepsin C Regulates Cytokine-Induced Apoptosis in β-Cell Model Systems10.3390/genes121116942073-4425https://doaj.org/article/a22d1491e7304840bd0de14a3c2616272021-10-01T00:00:00Zhttps://www.mdpi.com/2073-4425/12/11/1694https://doaj.org/toc/2073-4425Emerging evidence suggests that several of the lysosomal cathepsin proteases are genetically associated with type 1 diabetes (T1D) and participate in immune-mediated destruction of the pancreatic β cells. We previously reported that the T1D candidate gene cathepsin H is downregulated by pro-inflammatory cytokines in human pancreatic islets and regulates β-cell function, apoptosis, and disease progression in children with new-onset T1D. In the present study, the objective was to investigate the expression patterns of all 15 known cathepsins in β-cell model systems and examine their role in the regulation of cytokine-induced apoptosis. Real-time qPCR screening of the cathepsins in human islets, 1.1B4 and INS-1E β-cell models identified several cathepsins that were expressed and regulated by pro-inflammatory cytokines. Using small interfering RNAs to knock down (KD) the cytokine-regulated cathepsins, we identified an anti-apoptotic function of cathepsin C as KD increased cytokine-induced apoptosis. KD of cathepsin C correlated with increased phosphorylation of JNK and p38 mitogen-activated protein kinases, and elevated chemokine CXCL10/IP-10 expression. This study suggests that cathepsin C is a modulator of β-cell survival, and that immune modulation of cathepsin expression in islets may contribute to immune-mediated β-cell destruction in T1D.Tina FløyelCaroline FrørupJoachim StørlingFlemming PociotMDPI AGarticletype 1 diabeteslysosomal proteasesβ-cell deathCTSCMAPKCXCL10GeneticsQH426-470ENGenes, Vol 12, Iss 1694, p 1694 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	type 1 diabetes lysosomal proteases β-cell death CTSC MAPK CXCL10 Genetics QH426-470
spellingShingle	type 1 diabetes lysosomal proteases β-cell death CTSC MAPK CXCL10 Genetics QH426-470 Tina Fløyel Caroline Frørup Joachim Størling Flemming Pociot Cathepsin C Regulates Cytokine-Induced Apoptosis in β-Cell Model Systems
description	Emerging evidence suggests that several of the lysosomal cathepsin proteases are genetically associated with type 1 diabetes (T1D) and participate in immune-mediated destruction of the pancreatic β cells. We previously reported that the T1D candidate gene cathepsin H is downregulated by pro-inflammatory cytokines in human pancreatic islets and regulates β-cell function, apoptosis, and disease progression in children with new-onset T1D. In the present study, the objective was to investigate the expression patterns of all 15 known cathepsins in β-cell model systems and examine their role in the regulation of cytokine-induced apoptosis. Real-time qPCR screening of the cathepsins in human islets, 1.1B4 and INS-1E β-cell models identified several cathepsins that were expressed and regulated by pro-inflammatory cytokines. Using small interfering RNAs to knock down (KD) the cytokine-regulated cathepsins, we identified an anti-apoptotic function of cathepsin C as KD increased cytokine-induced apoptosis. KD of cathepsin C correlated with increased phosphorylation of JNK and p38 mitogen-activated protein kinases, and elevated chemokine CXCL10/IP-10 expression. This study suggests that cathepsin C is a modulator of β-cell survival, and that immune modulation of cathepsin expression in islets may contribute to immune-mediated β-cell destruction in T1D.
format	article
author	Tina Fløyel Caroline Frørup Joachim Størling Flemming Pociot
author_facet	Tina Fløyel Caroline Frørup Joachim Størling Flemming Pociot
author_sort	Tina Fløyel
title	Cathepsin C Regulates Cytokine-Induced Apoptosis in β-Cell Model Systems
title_short	Cathepsin C Regulates Cytokine-Induced Apoptosis in β-Cell Model Systems
title_full	Cathepsin C Regulates Cytokine-Induced Apoptosis in β-Cell Model Systems
title_fullStr	Cathepsin C Regulates Cytokine-Induced Apoptosis in β-Cell Model Systems
title_full_unstemmed	Cathepsin C Regulates Cytokine-Induced Apoptosis in β-Cell Model Systems
title_sort	cathepsin c regulates cytokine-induced apoptosis in β-cell model systems
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/a22d1491e7304840bd0de14a3c261627
work_keys_str_mv	AT tinafløyel cathepsincregulatescytokineinducedapoptosisinbcellmodelsystems AT carolinefrørup cathepsincregulatescytokineinducedapoptosisinbcellmodelsystems AT joachimstørling cathepsincregulatescytokineinducedapoptosisinbcellmodelsystems AT flemmingpociot cathepsincregulatescytokineinducedapoptosisinbcellmodelsystems
_version_	1718412120971804672

Cathepsin C Regulates Cytokine-Induced Apoptosis in β-Cell Model Systems

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