ERK controls epithelial cell death receptor signalling and cellular FLICE-like inhibitory protein (c-FLIP) in ulcerative colitis
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ERK controls epithelial cell death receptor signalling and cellular FLICE-like inhibitory protein (c-FLIP) in ulcerative colitis. / Seidelin, Jakob Benedict; Coskun, Mehmet; Vainer, Ben; Riis, Lene; Soendergaard, Christoffer; Nielsen, Ole Haagen.
In: Journal of Molecular Medicine, Vol. 91, No. 7, 07.2013, p. 839-49.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - ERK controls epithelial cell death receptor signalling and cellular FLICE-like inhibitory protein (c-FLIP) in ulcerative colitis
AU - Seidelin, Jakob Benedict
AU - Coskun, Mehmet
AU - Vainer, Ben
AU - Riis, Lene
AU - Soendergaard, Christoffer
AU - Nielsen, Ole Haagen
PY - 2013/7
Y1 - 2013/7
N2 - Intestinal epithelial cell (IEC) death signalling through the Fas receptor is impaired in active ulcerative colitis (UC). This is possibly due to the activation of cytoprotective pathways resulting in limitation of the tissue injury secondary to inflammation. We hypothesized that inflammatory signalling like the nuclear factor (NF)-κB or mitogen activated protein kinase (MAPK) pathways could be involved in (a) the modification of Fas mediated apoptosis responses and (b) the regulation of the Fas receptor inhibitor cellular FLICE-like inhibitory protein (c-FLIP). Phospho-ERK was upregulated in IECs in active UC as well as IECs exposed to pro-inflammatory cytokines in vitro. Similarly, the short form of c-FLIP (c-FLIPS) was found to be upregulated in IECs from patients with active UC. c-FLIPS was the main splice variant found in both HT-29 cells and primary human IECs. Both splice variants were induced by TNF-α, IL-1β and IFN-γ, while IL-10 induced c-FLIPL expression; TNF-α also induced c-FLIPS in primary IECs. Inhibition of NF-κB, JNK and p38 pathways did not affect c-FLIP expression, whereas ERK inhibition by MEK1 RNA silencing and pharmacologic inhibitors decreased c-FLIPS expression. Similarly, ERK - but not NF-κB - inhibited Fas ligand and TNF-α-mediated apoptosis responses in both cell line experiments and primary IECs. The present study identifies the MEK-ERK pathway as a major regulator of apoptosis in IECs during flares of UC and an inducer of c-FLIPS. The results explain the resistance to receptor mediated epithelial apoptosis in active UC. Oncogenic c-FLIP could promote propagation of DNA-damaged IECs and contribute to cancer development in UC.
AB - Intestinal epithelial cell (IEC) death signalling through the Fas receptor is impaired in active ulcerative colitis (UC). This is possibly due to the activation of cytoprotective pathways resulting in limitation of the tissue injury secondary to inflammation. We hypothesized that inflammatory signalling like the nuclear factor (NF)-κB or mitogen activated protein kinase (MAPK) pathways could be involved in (a) the modification of Fas mediated apoptosis responses and (b) the regulation of the Fas receptor inhibitor cellular FLICE-like inhibitory protein (c-FLIP). Phospho-ERK was upregulated in IECs in active UC as well as IECs exposed to pro-inflammatory cytokines in vitro. Similarly, the short form of c-FLIP (c-FLIPS) was found to be upregulated in IECs from patients with active UC. c-FLIPS was the main splice variant found in both HT-29 cells and primary human IECs. Both splice variants were induced by TNF-α, IL-1β and IFN-γ, while IL-10 induced c-FLIPL expression; TNF-α also induced c-FLIPS in primary IECs. Inhibition of NF-κB, JNK and p38 pathways did not affect c-FLIP expression, whereas ERK inhibition by MEK1 RNA silencing and pharmacologic inhibitors decreased c-FLIPS expression. Similarly, ERK - but not NF-κB - inhibited Fas ligand and TNF-α-mediated apoptosis responses in both cell line experiments and primary IECs. The present study identifies the MEK-ERK pathway as a major regulator of apoptosis in IECs during flares of UC and an inducer of c-FLIPS. The results explain the resistance to receptor mediated epithelial apoptosis in active UC. Oncogenic c-FLIP could promote propagation of DNA-damaged IECs and contribute to cancer development in UC.
KW - Adult
KW - Aged
KW - Aged, 80 and over
KW - CASP8 and FADD-Like Apoptosis Regulating Protein
KW - Colitis, Ulcerative
KW - Colon
KW - Cytokines
KW - Epithelial Cells
KW - Extracellular Signal-Regulated MAP Kinases
KW - HT29 Cells
KW - Humans
KW - Middle Aged
KW - Young Adult
U2 - 10.1007/s00109-013-1003-7
DO - 10.1007/s00109-013-1003-7
M3 - Journal article
C2 - 23371318
VL - 91
SP - 839
EP - 849
JO - Journal of Molecular Medicine
JF - Journal of Molecular Medicine
SN - 0946-2716
IS - 7
ER -
ID: 117546156