Cathepsin c regulates cytokine-induced apoptosis in β-cell model systems
Research output: Contribution to journal › Journal article › Research › peer-review
Standard
Cathepsin c regulates cytokine-induced apoptosis in β-cell model systems. / Fløyel, Tina; Frørup, Caroline; Størling, Joachim; Pociot, Flemming.
In: Genes, Vol. 12, No. 11, 1694, 2021.Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - Cathepsin c regulates cytokine-induced apoptosis in β-cell model systems
AU - Fløyel, Tina
AU - Frørup, Caroline
AU - Størling, Joachim
AU - Pociot, Flemming
N1 - Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - CTSC
KW - CXCL10
KW - Human pancreatic islets
KW - Inflammation
KW - Lysosomal proteases
KW - MAPK
KW - Pro-inflammatory cytokines
KW - Type 1 diabetes
KW - β-cell death
UR - http://www.scopus.com/inward/record.url?scp=85118486508&partnerID=8YFLogxK
U2 - 10.3390/genes12111694
DO - 10.3390/genes12111694
M3 - Journal article
C2 - 34828301
AN - SCOPUS:85118486508
VL - 12
JO - Genes
JF - Genes
SN - 2073-4425
IS - 11
M1 - 1694
ER -
ID: 284639178