TY - JOUR
T1 - HSPA6 is an ulcerative colitis susceptibility factor that is induced by cigarette smoke and protects intestinal epithelial cells by stabilizing anti-apoptotic Bcl-XL
AU - Regeling, Anouk
AU - Imhann, Floris
AU - Volders, Haukeline H
AU - Blokzijl, Tjasso
AU - Bloks, Vincent W
AU - Weersma, Rinse K
AU - Dijkstra, Gerard
AU - Faber, Klaas Nico
N1 - Copyright © 2016. Published by Elsevier B.V.
PY - 2016/4
Y1 - 2016/4
N2 - BACKGROUND: Cigarette smoking ameliorates ulcerative colitis (UC) and aggravates Crohn's disease (CD). Cigarette smoke suppresses inflammation-induced apoptosis in intestinal epithelial cells (DLD-1), which may explain its protective effect in UC. Here, we performed transcriptome profiling of cigarette smoke extract (CSE)-exposed DLD-1 and Jurkat cells (T-lymphocytes) and related this to UC susceptibility genes with protective functions in the intestinal epithelium.METHODS: CSE-regulated genes in DLD-1 and Jurkat cells were identified by Illumina microarrays and compared to genes in UC susceptibility loci. Colon biopsies were analyzed by immunohistochemistry for cell-specific expression of HSPA6. CSE-induced gene expression was analyzed by Q-PCR, Western blotting and immunofluorescence microscopy. Protein (HSPA6/Bcl-XL) interactions were analyzed by immunoprecipitation.RESULTS: CSE changed the expression of 536 and 2560 genes in DLD-1 and Jurkat cells, respectively. The "response to unfolded protein" was one of the most significantly affected gene sets with prominent induction (20.3-fold) of heat shock protein A6 (HSPA6). Six CSE-induced genes in DLD-1 cells were located in UC-susceptibility loci, including HSPA6 (rs1801274). HSPA6 is highly expressed in the human colonic epithelium. CSE caused a dose-dependent strong (>100-fold at 30% CSE for 6h), but transient induction of HSPA6 mRNA and protein in DLD-1 cells. HSPA6 co-immune precipitated with anti-apoptotic Bcl-XL, protein levels of which were increased while mRNA levels were unchanged.CONCLUSIONS: HSPA6 is a cigarette smoke-induced UC-susceptibility gene. The HSPA6 risk locus is associated with decreased HSPA6 expression. HSPA6 provides epithelial protection by stabilizing anti-apoptotic Bcl-XL, thereby contributing to the beneficial effect of cigarette smoking in UC.
AB - BACKGROUND: Cigarette smoking ameliorates ulcerative colitis (UC) and aggravates Crohn's disease (CD). Cigarette smoke suppresses inflammation-induced apoptosis in intestinal epithelial cells (DLD-1), which may explain its protective effect in UC. Here, we performed transcriptome profiling of cigarette smoke extract (CSE)-exposed DLD-1 and Jurkat cells (T-lymphocytes) and related this to UC susceptibility genes with protective functions in the intestinal epithelium.METHODS: CSE-regulated genes in DLD-1 and Jurkat cells were identified by Illumina microarrays and compared to genes in UC susceptibility loci. Colon biopsies were analyzed by immunohistochemistry for cell-specific expression of HSPA6. CSE-induced gene expression was analyzed by Q-PCR, Western blotting and immunofluorescence microscopy. Protein (HSPA6/Bcl-XL) interactions were analyzed by immunoprecipitation.RESULTS: CSE changed the expression of 536 and 2560 genes in DLD-1 and Jurkat cells, respectively. The "response to unfolded protein" was one of the most significantly affected gene sets with prominent induction (20.3-fold) of heat shock protein A6 (HSPA6). Six CSE-induced genes in DLD-1 cells were located in UC-susceptibility loci, including HSPA6 (rs1801274). HSPA6 is highly expressed in the human colonic epithelium. CSE caused a dose-dependent strong (>100-fold at 30% CSE for 6h), but transient induction of HSPA6 mRNA and protein in DLD-1 cells. HSPA6 co-immune precipitated with anti-apoptotic Bcl-XL, protein levels of which were increased while mRNA levels were unchanged.CONCLUSIONS: HSPA6 is a cigarette smoke-induced UC-susceptibility gene. The HSPA6 risk locus is associated with decreased HSPA6 expression. HSPA6 provides epithelial protection by stabilizing anti-apoptotic Bcl-XL, thereby contributing to the beneficial effect of cigarette smoking in UC.
KW - Ulcerative colitis
KW - Cigarette smoke
KW - Intestinal epithelium
KW - Heat shock protein A6
KW - Apoptosis
KW - HEAT-SHOCK PROTEINS
KW - INFLAMMATORY-BOWEL-DISEASE
KW - ACID-INDUCED COLITIS
KW - GASTROINTESTINAL-DISEASES
KW - PHYSIOLOGICAL EXPRESSION
KW - TRANSLATIONAL INHIBITION
KW - COLON-CANCER
KW - RISK LOCI
KW - HEAT-SHOCK-PROTEIN-70
KW - GERANYLGERANYLACETONE
U2 - 10.1016/j.bbadis.2016.01.020
DO - 10.1016/j.bbadis.2016.01.020
M3 - Article
C2 - 26826017
SN - 0925-4439
VL - 1862
SP - 788
EP - 796
JO - Biochimica et biophysica acta-Molecular basis of disease
JF - Biochimica et biophysica acta-Molecular basis of disease
IS - 4
ER -