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HSPA6 is an ulcerative colitis susceptibility factor that is induced by cigarette smoke and protects intestinal epithelial cells by stabilizing anti-apoptotic Bcl-XL

Regeling, A., Imhann, F., Volders, H. H., Blokzijl, T., Bloks, V. W., Weersma, R. K., Dijkstra, G. & Faber, K. N., Apr-2016, In : Biochimica et biophysica acta-Molecular basis of disease. 1862, 4, p. 788-796 9 p.

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  • HSPA6 is an ulcerative colitis susceptibility factor that is induced by cigarette smoke and protects intestinal epithelial

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DOI

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.

Original languageEnglish
Pages (from-to)788-796
Number of pages9
JournalBiochimica et biophysica acta-Molecular basis of disease
Volume1862
Issue number4
Publication statusPublished - Apr-2016

    Keywords

  • Ulcerative colitis, Cigarette smoke, Intestinal epithelium, Heat shock protein A6, Apoptosis, HEAT-SHOCK PROTEINS, INFLAMMATORY-BOWEL-DISEASE, ACID-INDUCED COLITIS, GASTROINTESTINAL-DISEASES, PHYSIOLOGICAL EXPRESSION, TRANSLATIONAL INHIBITION, COLON-CANCER, RISK LOCI, HEAT-SHOCK-PROTEIN-70, GERANYLGERANYLACETONE

ID: 28252256