Cellular inhibitor of apoptosis protein 2 controls human colonic epithelial restitution, migration, and Rac1 activation

Jakob Benedict Seidelin; Sylvester Larsen; Dorte Linnemann; Ben Vainer; Mehmet Coskun; Jesper Thorvald Troelsen; Ole Haagen Nielsen

doi:10.1152/ajpgi.00089.2014

Cellular inhibitor of apoptosis protein 2 controls human colonic epithelial restitution, migration, and Rac1 activation

Jakob Benedict Seidelin, Sylvester Larsen, Dorte Linnemann, Ben Vainer, Mehmet Coskun, Jesper Thorvald Troelsen, Ole Haagen Nielsen

12 Citations (Scopus)

Abstract

Identification of pathways involved in wound healing is important for understanding the pathogenesis of various intestinal diseases. Cellular inhibitor of apoptosis protein 2 (cIAP2) regulates proliferation and migration in nonepithelial cells and is expressed in human colonocytes. The aim of the study was to investigate the role of cIAP2 for wound healing in the normal human colon. Wound tissue was generated by taking rectosigmoidal biopsies across an experimental ulcer in healthy subjects after 5, 24, and 48 h. In experimental ulcers, the expression of cIAP2 in regenerating intestinal epithelial cells (IECs) was increased at the wound edge after 24 h (P < 0.05), returned to normal after reepithelialization, and correlated with the inflammatory reaction in the experimental wounds (P < 0.001). cIAP2 was induced in vitro in regenerating Caco2 IECs after wound infliction (P < 0.01). Knockdown of cIAP2 caused a substantial impairment of the IEC regeneration through inhibition of migration (P < 0.005). cIAP2 overexpression lead to formation of migrating IECs and upregulation of expression of RhoA and Rac1 as well as GTP-activation of Rac1. Transforming growth factor-β1 enhanced the expression of cIAP2 but was not upregulated in wounds in vivo and in vitro. NF-κB and MAPK pathways did not affect cIAP2 expression. cIAP2 is in conclusion a regulator of human intestinal wound healing through enhanced migration along with activation of Rac1, and the findings suggest that cIAP2 could be a future therapeutic target to improve intestinal wound healing.

Original language	English
Journal	American Journal of Physiology: Gastrointestinal and Liver Physiology
Volume	308
Issue number	2
Pages (from-to)	G92-G99
Number of pages	8
ISSN	0193-1857
DOIs	https://doi.org/10.1152/ajpgi.00089.2014
Publication status	Published - 15 Jan 2015

Keywords

Apoptosis
Cell Line
Cell Movement
Colon
Enzyme Activation
Epithelial Cells
Humans
Inhibitor of Apoptosis Proteins
Intestinal Mucosa
NF-kappa B
Transforming Growth Factor beta1
Ubiquitin-Protein Ligases
Wound Healing
rac1 GTP-Binding Protein

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1152/ajpgi.00089.2014

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Cellular inhibitor of apoptosis protein 2 controls human colonic epithelial restitution, migration, and Rac1 activation. / Seidelin, Jakob Benedict; Larsen, Sylvester; Linnemann, Dorte et al.

In: American Journal of Physiology: Gastrointestinal and Liver Physiology, Vol. 308, No. 2, 15.01.2015, p. G92-G99.

Research output: Contribution to journal › Journal article › Research › peer-review

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title = "Cellular inhibitor of apoptosis protein 2 controls human colonic epithelial restitution, migration, and Rac1 activation",

abstract = "Identification of pathways involved in wound healing is important for understanding the pathogenesis of various intestinal diseases. Cellular inhibitor of apoptosis protein 2 (cIAP2) regulates proliferation and migration in nonepithelial cells and is expressed in human colonocytes. The aim of the study was to investigate the role of cIAP2 for wound healing in the normal human colon. Wound tissue was generated by taking rectosigmoidal biopsies across an experimental ulcer in healthy subjects after 5, 24, and 48 h. In experimental ulcers, the expression of cIAP2 in regenerating intestinal epithelial cells (IECs) was increased at the wound edge after 24 h (P < 0.05), returned to normal after reepithelialization, and correlated with the inflammatory reaction in the experimental wounds (P < 0.001). cIAP2 was induced in vitro in regenerating Caco2 IECs after wound infliction (P < 0.01). Knockdown of cIAP2 caused a substantial impairment of the IEC regeneration through inhibition of migration (P < 0.005). cIAP2 overexpression lead to formation of migrating IECs and upregulation of expression of RhoA and Rac1 as well as GTP-activation of Rac1. Transforming growth factor-β1 enhanced the expression of cIAP2 but was not upregulated in wounds in vivo and in vitro. NF-κB and MAPK pathways did not affect cIAP2 expression. cIAP2 is in conclusion a regulator of human intestinal wound healing through enhanced migration along with activation of Rac1, and the findings suggest that cIAP2 could be a future therapeutic target to improve intestinal wound healing.",

keywords = "Apoptosis, Cell Line, Cell Movement, Colon, Enzyme Activation, Epithelial Cells, Humans, Inhibitor of Apoptosis Proteins, Intestinal Mucosa, NF-kappa B, Transforming Growth Factor beta1, Ubiquitin-Protein Ligases, Wound Healing, rac1 GTP-Binding Protein",

author = "Seidelin, {Jakob Benedict} and Sylvester Larsen and Dorte Linnemann and Ben Vainer and Mehmet Coskun and Troelsen, {Jesper Thorvald} and Nielsen, {Ole Haagen}",

note = "Copyright {\textcopyright} 2015 the American Physiological Society.",

year = "2015",

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doi = "10.1152/ajpgi.00089.2014",

language = "English",

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TY - JOUR

T1 - Cellular inhibitor of apoptosis protein 2 controls human colonic epithelial restitution, migration, and Rac1 activation

AU - Seidelin, Jakob Benedict

AU - Larsen, Sylvester

AU - Linnemann, Dorte

AU - Vainer, Ben

AU - Coskun, Mehmet

AU - Troelsen, Jesper Thorvald

AU - Nielsen, Ole Haagen

PY - 2015/1/15

Y1 - 2015/1/15

N2 - Identification of pathways involved in wound healing is important for understanding the pathogenesis of various intestinal diseases. Cellular inhibitor of apoptosis protein 2 (cIAP2) regulates proliferation and migration in nonepithelial cells and is expressed in human colonocytes. The aim of the study was to investigate the role of cIAP2 for wound healing in the normal human colon. Wound tissue was generated by taking rectosigmoidal biopsies across an experimental ulcer in healthy subjects after 5, 24, and 48 h. In experimental ulcers, the expression of cIAP2 in regenerating intestinal epithelial cells (IECs) was increased at the wound edge after 24 h (P < 0.05), returned to normal after reepithelialization, and correlated with the inflammatory reaction in the experimental wounds (P < 0.001). cIAP2 was induced in vitro in regenerating Caco2 IECs after wound infliction (P < 0.01). Knockdown of cIAP2 caused a substantial impairment of the IEC regeneration through inhibition of migration (P < 0.005). cIAP2 overexpression lead to formation of migrating IECs and upregulation of expression of RhoA and Rac1 as well as GTP-activation of Rac1. Transforming growth factor-β1 enhanced the expression of cIAP2 but was not upregulated in wounds in vivo and in vitro. NF-κB and MAPK pathways did not affect cIAP2 expression. cIAP2 is in conclusion a regulator of human intestinal wound healing through enhanced migration along with activation of Rac1, and the findings suggest that cIAP2 could be a future therapeutic target to improve intestinal wound healing.

AB - Identification of pathways involved in wound healing is important for understanding the pathogenesis of various intestinal diseases. Cellular inhibitor of apoptosis protein 2 (cIAP2) regulates proliferation and migration in nonepithelial cells and is expressed in human colonocytes. The aim of the study was to investigate the role of cIAP2 for wound healing in the normal human colon. Wound tissue was generated by taking rectosigmoidal biopsies across an experimental ulcer in healthy subjects after 5, 24, and 48 h. In experimental ulcers, the expression of cIAP2 in regenerating intestinal epithelial cells (IECs) was increased at the wound edge after 24 h (P < 0.05), returned to normal after reepithelialization, and correlated with the inflammatory reaction in the experimental wounds (P < 0.001). cIAP2 was induced in vitro in regenerating Caco2 IECs after wound infliction (P < 0.01). Knockdown of cIAP2 caused a substantial impairment of the IEC regeneration through inhibition of migration (P < 0.005). cIAP2 overexpression lead to formation of migrating IECs and upregulation of expression of RhoA and Rac1 as well as GTP-activation of Rac1. Transforming growth factor-β1 enhanced the expression of cIAP2 but was not upregulated in wounds in vivo and in vitro. NF-κB and MAPK pathways did not affect cIAP2 expression. cIAP2 is in conclusion a regulator of human intestinal wound healing through enhanced migration along with activation of Rac1, and the findings suggest that cIAP2 could be a future therapeutic target to improve intestinal wound healing.

KW - Apoptosis

KW - Cell Line

KW - Cell Movement

KW - Colon

KW - Enzyme Activation

KW - Epithelial Cells

KW - Humans

KW - Inhibitor of Apoptosis Proteins

KW - Intestinal Mucosa

KW - NF-kappa B

KW - Transforming Growth Factor beta1

KW - Ubiquitin-Protein Ligases

KW - Wound Healing

KW - rac1 GTP-Binding Protein

U2 - 10.1152/ajpgi.00089.2014

DO - 10.1152/ajpgi.00089.2014

M3 - Journal article

C2 - 25394657

SN - 0193-1857

VL - 308

SP - G92-G99

JO - American Journal of Physiology: Gastrointestinal and Liver Physiology

JF - American Journal of Physiology: Gastrointestinal and Liver Physiology

IS - 2

ER -

Cellular inhibitor of apoptosis protein 2 controls human colonic epithelial restitution, migration, and Rac1 activation

Abstract

Keywords

UN SDGs

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