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

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 CSE-induced gene expression was analyzed by Q-PCR, Western blotting and immunofluorescence microscopy. Protein 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 Six CSE-induced genes in DLD-1 cells were located in UC-susceptibility loci, including (rs1801274). Hduanyu18426 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 Hduanyu18426 mRNA and protein in DLD-1 cells. Hduanyu18426 co-immune precipitated with anti-apoptotic Bcl-XL, protein levels of which were increased while mRNA levels were is a cigarette smoke-induced UC-susceptibility gene. The Hduanyu18426 risk locus is associated with decreased Hduanyu18426 expression. Hduanyu18426 provides epithelial protection by stabilizing anti-apoptotic Bcl-XL, thereby contributing to the beneficial effect of cigarette smoking in UC.

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