BACKGROUND: IL-33 is a new tissue-derived cytokine constitutively expressed in epithelial cells and plays a role in sensing damage caused by inflammatory diseases. The function of IL-33 in the esophageal mucosa has not been previously described. Accordingly, we examined the expression of IL-33 and its role in the pathogenesis of reflux esophagitis (RE). METHODS: IL-33 in the esophageal mucosa of RE patients and in an in vitro stratified normal esophageal squamous epithelial model was examined at the messenger RNA and protein levels. The correlation of the level of IL-33 and IL-8 or IL-6 was examined. Cell layers were stimulated with bile acids and cytokines. IL-33 was knocked down by small interfering RNA (siRNA). Pharmacological inhibitors and signal transducer and activator of transcription 1 (STAT1) siRNA were used. RESULTS: IL-33 was significantly upregulated in RE patients, and was located in the nuclei of basal and suprabasal layers. Upregulated IL-33 messenger RNA expression was correlated with IL-8 and IL-6 expression. In vitro, IL-33 was upregulated in the nuclei of basal and suprabasal layers by interferon-γ (IFNγ), and the upregulation was aggravated by the combination of deoxycholic acid (DCA) and IFNγ. IL-33 knockdown dampened IFNγ- and DCA-induced IL-8 and IL-6 production. IFNγ-induced IL-33 was inhibited by a Janus kinase inhibitor, a p38 mitogen-activated protein kinase inhibitor, and STAT1 siRNA. CONCLUSIONS: Nuclear IL-33 is upregulated in erosive mucosa of RE patients and is correlated with IL-8 and IL-6 levels. The normal esophageal epithelial model enables us to show for the first time that epithelial-cell-derived nuclear but not exogenous IL-33 is located upstream of the production of inflammatory cytokines and can aggravate the inflammation.
BACKGROUND:IL-33 is a new tissue-derived cytokine constitutively expressed in epithelial cells and plays a role in sensing damage caused by inflammatory diseases. The function of IL-33 in the esophageal mucosa has not been previously described. Accordingly, we examined the expression of IL-33 and its role in the pathogenesis of reflux esophagitis (RE). METHODS:IL-33 in the esophageal mucosa of RE patients and in an in vitro stratified normal esophageal squamous epithelial model was examined at the messenger RNA and protein levels. The correlation of the level of IL-33 and IL-8 or IL-6 was examined. Cell layers were stimulated with bile acids and cytokines. IL-33 was knocked down by small interfering RNA (siRNA). Pharmacological inhibitors and signal transducer and activator of transcription 1 (STAT1) siRNA were used. RESULTS:IL-33 was significantly upregulated in RE patients, and was located in the nuclei of basal and suprabasal layers. Upregulated IL-33 messenger RNA expression was correlated with IL-8 and IL-6 expression. In vitro, IL-33 was upregulated in the nuclei of basal and suprabasal layers by interferon-γ (IFNγ), and the upregulation was aggravated by the combination of deoxycholic acid (DCA) and IFNγ. IL-33 knockdown dampened IFNγ- and DCA-induced IL-8 and IL-6 production. IFNγ-induced IL-33 was inhibited by a Janus kinase inhibitor, a p38 mitogen-activated protein kinase inhibitor, and STAT1 siRNA. CONCLUSIONS: Nuclear IL-33 is upregulated in erosive mucosa of RE patients and is correlated with IL-8 and IL-6 levels. The normal esophageal epithelial model enables us to show for the first time that epithelial-cell-derived nuclear but not exogenous IL-33 is located upstream of the production of inflammatory cytokines and can aggravate the inflammation.
Authors: Biljana Jovov; Jianwen Que; Nelia A Tobey; Zorka Djukic; Brigid L M Hogan; Roy C Orlando Journal: Am J Gastroenterol Date: 2011-03-29 Impact factor: 10.864
Authors: M Sakashita; T Yoshimoto; T Hirota; M Harada; K Okubo; Y Osawa; S Fujieda; Y Nakamura; K Yasuda; K Nakanishi; M Tamari Journal: Clin Exp Allergy Date: 2008-12 Impact factor: 5.018
Authors: Allison Lange; Ryan E Mills; Christopher J Lange; Murray Stewart; Scott E Devine; Anita H Corbett Journal: J Biol Chem Date: 2006-12-14 Impact factor: 5.157
Authors: Racha T Khalaf; Glenn T Furuta; Brandie D Wagner; Charles E Robertson; Rachel Andrews; Mark J Stevens; Sophie A Fillon; Edith T Zemanick; J Kirk Harris Journal: J Pediatr Gastroenterol Nutr Date: 2021-04-01 Impact factor: 2.839
Authors: Michael B Soyka; David Holzmann; Tomasz M Basinski; Marcin Wawrzyniak; Christina Bannert; Simone Bürgler; Tunc Akkoc; Angela Treis; Beate Rückert; Mübeccel Akdis; Cezmi A Akdis; Thomas Eiwegger Journal: PLoS One Date: 2015-05-01 Impact factor: 3.240