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Enterocyte STAT5 promotes mucosal wound healing via suppression of myosin light chain kinase-mediated loss of barrier function and inflammation.

Gilbert S, Zhang R, Denson L, Moriggl R, Steinbrecher K, Shroyer N, Lin J, Han X - EMBO Mol Med (2012)

Bottom Line: Consistently, knockdown of stat5 in IEC monolayers led to increased NF-κB DNA binding to MLCK promoter, myosin light chain phosphorylation and tight junction (TJ) permeability, which were potentiated by administration of tumour necrosis factor-α (TNF-α), and prevented by concurrent NF-κB knockdown.Collectively, enterocyte STAT5 signalling protects against TJ barrier dysfunction and promotes intestinal mucosal wound healing via an interaction with NF-κB to suppress MLCK.Targeting IEC STAT5 signalling may be a novel therapeutic approach for treating intestinal barrier dysfunction in IBD.

View Article: PubMed Central - PubMed

Affiliation: Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, OH, USA.

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STAT5 in IECs regulates NF-κB activation in response to gut injuryMice were treated with 3% DSS for 5 days followed by 5 days of water. Colonic mucosa was extracted, and NE and CE recovered.A,B. p65 nuclear abundance was determined in NE (A), and IκBα and Iκβ were detected in CE (B). Signal intensity was determined by densitometry, results were expressed as the mean ± SEM (n = 5). *p < 0.05 versus STAT5IEC WT mice, #p < 0.05 versus STAT5IEC WT mice in the water recovery group.C. IECs were isolated from STAT5IEC WT and STAT5IEC KO mice, p65 nuclear abundances were determined by WB.D. Colon sections were immunostained with phosphoserine p65 (P-p65) as indicated by arrows. Results were expressed as average positive cells per crypt, n = 5, bar = 100 µm.
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fig04: STAT5 in IECs regulates NF-κB activation in response to gut injuryMice were treated with 3% DSS for 5 days followed by 5 days of water. Colonic mucosa was extracted, and NE and CE recovered.A,B. p65 nuclear abundance was determined in NE (A), and IκBα and Iκβ were detected in CE (B). Signal intensity was determined by densitometry, results were expressed as the mean ± SEM (n = 5). *p < 0.05 versus STAT5IEC WT mice, #p < 0.05 versus STAT5IEC WT mice in the water recovery group.C. IECs were isolated from STAT5IEC WT and STAT5IEC KO mice, p65 nuclear abundances were determined by WB.D. Colon sections were immunostained with phosphoserine p65 (P-p65) as indicated by arrows. Results were expressed as average positive cells per crypt, n = 5, bar = 100 µm.

Mentions: NF-κB activation promotes chronic intestinal inflammation in both CD and UC (Han et al, 2006; Schreiber et al, 1998). Our data exhibited that nuclear levels of RelA/p65 remained at significantly higher levels in the colonic mucosa of STAT5IEC KO mice than in littermate controls either under basal conditions or during water recovery after the cessation of DSS (Fig 4A). In addition, colonic IκBα expression, an endogenous suppressor of NF-κB activity, was consistently and remarkably reduced under basal conditions or in the water recovery group in STAT5IEC KO mice compared to STAT5IEC WT mice (Fig 4B). Most importantly, our data exhibited that depletion of IEC STAT5 in mice increased basal NF-κB activity in IECs, as determined by the nuclear abundance and phosphorylation of RelA/p65 (Fig 4C and D). Together, these data suggest that there is an interaction between IEC STAT5 and NF-κB in the regulation of the intestinal immune response to injury. IEC STAT5 could suppress NF-κB nuclear activation by stabilizing IκBα to ameliorate mucosal inflammation (STAT5 → IκBα⊣ NF-κB).


Enterocyte STAT5 promotes mucosal wound healing via suppression of myosin light chain kinase-mediated loss of barrier function and inflammation.

Gilbert S, Zhang R, Denson L, Moriggl R, Steinbrecher K, Shroyer N, Lin J, Han X - EMBO Mol Med (2012)

STAT5 in IECs regulates NF-κB activation in response to gut injuryMice were treated with 3% DSS for 5 days followed by 5 days of water. Colonic mucosa was extracted, and NE and CE recovered.A,B. p65 nuclear abundance was determined in NE (A), and IκBα and Iκβ were detected in CE (B). Signal intensity was determined by densitometry, results were expressed as the mean ± SEM (n = 5). *p < 0.05 versus STAT5IEC WT mice, #p < 0.05 versus STAT5IEC WT mice in the water recovery group.C. IECs were isolated from STAT5IEC WT and STAT5IEC KO mice, p65 nuclear abundances were determined by WB.D. Colon sections were immunostained with phosphoserine p65 (P-p65) as indicated by arrows. Results were expressed as average positive cells per crypt, n = 5, bar = 100 µm.
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Related In: Results  -  Collection

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fig04: STAT5 in IECs regulates NF-κB activation in response to gut injuryMice were treated with 3% DSS for 5 days followed by 5 days of water. Colonic mucosa was extracted, and NE and CE recovered.A,B. p65 nuclear abundance was determined in NE (A), and IκBα and Iκβ were detected in CE (B). Signal intensity was determined by densitometry, results were expressed as the mean ± SEM (n = 5). *p < 0.05 versus STAT5IEC WT mice, #p < 0.05 versus STAT5IEC WT mice in the water recovery group.C. IECs were isolated from STAT5IEC WT and STAT5IEC KO mice, p65 nuclear abundances were determined by WB.D. Colon sections were immunostained with phosphoserine p65 (P-p65) as indicated by arrows. Results were expressed as average positive cells per crypt, n = 5, bar = 100 µm.
Mentions: NF-κB activation promotes chronic intestinal inflammation in both CD and UC (Han et al, 2006; Schreiber et al, 1998). Our data exhibited that nuclear levels of RelA/p65 remained at significantly higher levels in the colonic mucosa of STAT5IEC KO mice than in littermate controls either under basal conditions or during water recovery after the cessation of DSS (Fig 4A). In addition, colonic IκBα expression, an endogenous suppressor of NF-κB activity, was consistently and remarkably reduced under basal conditions or in the water recovery group in STAT5IEC KO mice compared to STAT5IEC WT mice (Fig 4B). Most importantly, our data exhibited that depletion of IEC STAT5 in mice increased basal NF-κB activity in IECs, as determined by the nuclear abundance and phosphorylation of RelA/p65 (Fig 4C and D). Together, these data suggest that there is an interaction between IEC STAT5 and NF-κB in the regulation of the intestinal immune response to injury. IEC STAT5 could suppress NF-κB nuclear activation by stabilizing IκBα to ameliorate mucosal inflammation (STAT5 → IκBα⊣ NF-κB).

Bottom Line: Consistently, knockdown of stat5 in IEC monolayers led to increased NF-κB DNA binding to MLCK promoter, myosin light chain phosphorylation and tight junction (TJ) permeability, which were potentiated by administration of tumour necrosis factor-α (TNF-α), and prevented by concurrent NF-κB knockdown.Collectively, enterocyte STAT5 signalling protects against TJ barrier dysfunction and promotes intestinal mucosal wound healing via an interaction with NF-κB to suppress MLCK.Targeting IEC STAT5 signalling may be a novel therapeutic approach for treating intestinal barrier dysfunction in IBD.

View Article: PubMed Central - PubMed

Affiliation: Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, OH, USA.

Show MeSH
Related in: MedlinePlus