title: IL-10 promotes production of intestinal mucus by suppressing protein misfolding and endoplasmic reticulum stress in goblet cells.
abstract: OBJECTIVE
  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.affiliation: Immunity, Infection and Inflammation Program, Mater Medical Research Institute, Mater Health Services and the University of Queensland, South Brisbane, Queensland, Australia.
authors.forename: Sumaira Z
authors.initials: SZ
authors.lastname: Hasnain
authors.affiliation: Immunity, Infection and Inflammation Program, Mater Medical Research Institute, Mater Health Services and the University of Queensland, South Brisbane, Queensland, Australia.
authors.forename: Sharyn
authors.initials: S
authors.lastname: Tauro
authors.affiliation: Immunity, Infection and Inflammation Program, Mater Medical Research Institute, Mater Health Services and the University of Queensland, South Brisbane, Queensland, Australia.
authors.forename: Indrajit
authors.initials: I
authors.lastname: Das
authors.affiliation: Immunity, Infection and Inflammation Program, Mater Medical Research Institute, Mater Health Services and the University of Queensland, South Brisbane, Queensland, Australia.
authors.forename: Hui
authors.initials: H
authors.lastname: Tong
authors.affiliation: Immunity, Infection and Inflammation Program, Mater Medical Research Institute, Mater Health Services and the University of Queensland, South Brisbane, Queensland, Australia.
authors.forename: Alice C-H
authors.initials: AC
authors.lastname: Chen
authors.affiliation: Immunity, Infection and Inflammation Program, Mater Medical Research Institute, Mater Health Services and the University of Queensland, South Brisbane, Queensland, Australia.
authors.forename: Penny L
authors.initials: PL
authors.lastname: Jeffery
authors.affiliation: Immunity, Infection and Inflammation Program, Mater Medical Research Institute, Mater Health Services and the University of Queensland, South Brisbane, Queensland, Australia.
authors.forename: Victoria
authors.initials: V
authors.lastname: McDonald
authors.affiliation: Immunity, Infection and Inflammation Program, Mater Medical Research Institute, Mater Health Services and the University of Queensland, South Brisbane, Queensland, Australia.
authors.forename: Timothy H
authors.initials: TH
authors.lastname: Florin
authors.affiliation: Immunity, Infection and Inflammation Program, Mater Medical Research Institute, Mater Health Services and the University of Queensland, South Brisbane, Queensland, Australia. Electronic address: mmcguckin@mmri.mater.org.au.
authors.forename: Michael A
authors.initials: MA
authors.lastname: McGuckin
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D020397:Goblet Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D016753:Interleukin-10 / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009093:Mucus / Q000187:drug effects / Q000378:metabolism*; D057165:Proteostasis Deficiencies / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D016753:Interleukin-10