Tumor necrosis factor suppresses NR5A2 activity and intestinal glucocorticoid synthesis to sustain chronic colitis

Sheng Chieh Huang, Cheng Tse Lee, Bon Chu Chung

Research output: Contribution to journalArticlepeer-review

24 Citations (Scopus)

Abstract

Intestinal crypt epithelial cells synthesize glucocorticoids, steroid hormones that protect against inflammatory bowel disease. To investigatehowintestinal glucocorticoids are regulated during chronic inflammation, weinduced chronic colitis in mice by exposing themto the chemical dextran sulfate sodium (DSS).Wefound that intestinal glucocorticoid secretion and expression of the genes Cyp11a1 and Cyp11b1 (which encode enzymes that synthesize glucocorticoids) were initially stimulated, but declined during the chronic phase, whereas tumor necrosis factor (TNF) and inflammatory cytokines secreted by T helper type 1 (TH1) and TH17 cells continuously increased in abundance in the inflamed colon. This suggested that inadequate intestinal glucocorticoid synthesis is a feature of chronic intestinal inflammation. Wescreened for cytokines that regulated intestinal glucocorticoid synthesis and found that TNF suppressed corticosterone secretion and Cyp11a1 and Cyp11b1 expression in an intestinal crypt epithelial cell line. TNF suppressed steroidogenesis by activating the transcription factors c-Jun and nuclear factor kB (NF-kB),which both interacted with the transcription factorNR5A2and repressed Cyp11a1 reporter activity. This repressionwas relieved by expression of a dominant-negative form of c-Jun amino-terminal kinase 1 (JNK1), inhibitor of NF-kB, or by a JNK inhibitor. Furthermore, the dominant-negative TNF inhibitor XPro1595 inhibited c-Jun and NF-kB activation in mice, restored intestinal Cyp11a1 and Cyp11b1 expression, reduced colonic cell death, and rescued chronic colitis caused by DSS. Thus, during chronic colitis, TNF suppresses intestinal steroidogenic gene expression by inhibiting the activity of NR5A2, thus decreasing glucocorticoid synthesis and sustaining chronic inflammation.

Original languageEnglish
JournalScience Signaling
Volume7
Issue number314
DOIs
Publication statusPublished - Feb 25 2014

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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