BACKGROUND & AIMS: Protein misfolding and endoplasmic reticulum (ER) stress have been observed in intestinal secretory cells from patients with inflammatory bowel diseases and induce intestinal inflammation in mice. However, it is not clear how immune factors affect ER stress and therefore disease symptoms. METHODS: We analyzed the effects of interleukin (IL)-10 on ER stress in intestinal tissues in wild-type C57BL/6, Winnie, IL-10(-/-), and Winnie × IL-10(+/-) mice. In Winnie mice, misfolding of the intestinal mucin Muc2 initiates ER stress and inflammation. We also analyzed the effects of different inhibitors of IL-10 signaling and the N-glycosylation inhibitor tunicamycin in cultured human LS174T goblet cells. RESULTS: Administration of neutralizing antibodies against IL-10 or its receptor (IL-10R1) to Winnie mice rapidly exacerbated ER stress and intestinal inflammation compared with mice given vehicle (controls). Antibodies against IL-10 also increased accumulation of misfolded Muc2 in the ER of goblet cells of Winnie mice and increased T-cell production of inflammatory cytokines. Winnie × IL-10(+/-) mice and IL-10(-/-) mice with a single Winnie allele each developed more severe inflammation than Winnie mice or IL-10(-/-) mice. Administration of tunicamycin to wild-type mice caused intestinal ER stress, which increased when IL-10R1 was blocked. In LS174T cells, induction of ER stress with tunicamycin and misfolding of MUC2 were reduced by administration of IL-10; this reduction required STAT1 and STAT3. In LS174T cells incubated with tunicamycin, IL-10 up-regulated genes involved in MUC2 folding and in ER-associated degradation and maintained correct folding of MUC2, its transport from the ER, and its O-glycosylation and secretion. CONCLUSIONS: IL-10 prevents protein misfolding and ER stress by maintaining mucin production in goblet cells and helps the intestine preserve the mucus barrier.
BACKGROUND & AIMS: Protein misfolding and endoplasmic reticulum (ER) stress have been observed in intestinal secretory cells from patients with inflammatory bowel diseases and induce intestinal inflammation in mice. However, it is not clear how immune factors affect ER stress and therefore disease symptoms. METHODS: We analyzed the effects of interleukin (IL)-10 on ER stress in intestinal tissues in wild-type C57BL/6, Winnie, IL-10(-/-), and Winnie × IL-10(+/-) mice. In Winnie mice, misfolding of the intestinal mucin Muc2 initiates ER stress and inflammation. We also analyzed the effects of different inhibitors of IL-10 signaling and the N-glycosylation inhibitor tunicamycin in cultured human LS174T goblet cells. RESULTS: Administration of neutralizing antibodies against IL-10 or its receptor (IL-10R1) to Winnie mice rapidly exacerbated ER stress and intestinal inflammation compared with mice given vehicle (controls). Antibodies against IL-10 also increased accumulation of misfolded Muc2 in the ER of goblet cells of Winnie mice and increased T-cell production of inflammatory cytokines. Winnie × IL-10(+/-) mice and IL-10(-/-) mice with a single Winnie allele each developed more severe inflammation than Winnie mice or IL-10(-/-) mice. Administration of tunicamycin to wild-type mice caused intestinal ER stress, which increased when IL-10R1 was blocked. In LS174T cells, induction of ER stress with tunicamycin and misfolding of MUC2 were reduced by administration of IL-10; this reduction required STAT1 and STAT3. In LS174T cells incubated with tunicamycin, IL-10 up-regulated genes involved in MUC2 folding and in ER-associated degradation and maintained correct folding of MUC2, its transport from the ER, and its O-glycosylation and secretion. CONCLUSIONS:IL-10 prevents protein misfolding and ER stress by maintaining mucin production in goblet cells and helps the intestine preserve the mucus barrier.
Authors: Sumaira Z Hasnain; Danielle J Borg; Brooke E Harcourt; Hui Tong; Yonghua H Sheng; Choa Ping Ng; Indrajit Das; Ran Wang; Alice C-H Chen; Thomas Loudovaris; Thomas W Kay; Helen E Thomas; Jonathan P Whitehead; Josephine M Forbes; Johannes B Prins; Michael A McGuckin Journal: Nat Med Date: 2014-11-02 Impact factor: 53.440
Authors: Daniel B Graham; Ariel Lefkovith; Patrick Deelen; Niek de Klein; Mukund Varma; Angela Boroughs; A Nicole Desch; Aylwin C Y Ng; Gaelen Guzman; Monica Schenone; Christine P Petersen; Atul K Bhan; Manuel A Rivas; Mark J Daly; Steven A Carr; Cisca Wijmenga; Ramnik J Xavier Journal: Cell Rep Date: 2016-12-13 Impact factor: 9.423
Authors: Valentina Volynets; Andreas Rings; Gyöngyi Bárdos; Maureen J Ostaff; Jan Wehkamp; Stephan C Bischoff Journal: Tissue Barriers Date: 2016-07-08
Authors: Marta Wlodarska; Chengwei Luo; Raivo Kolde; Eva d'Hennezel; John W Annand; Cortney E Heim; Philipp Krastel; Esther K Schmitt; Abdifatah S Omar; Elizabeth A Creasey; Ashley L Garner; Sina Mohammadi; Daniel J O'Connell; Sahar Abubucker; Timothy D Arthur; Eric A Franzosa; Curtis Huttenhower; Leon O Murphy; Henry J Haiser; Hera Vlamakis; Jeffrey A Porter; Ramnik J Xavier Journal: Cell Host Microbe Date: 2017-07-12 Impact factor: 21.023