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

Sci Signal. 2014 Feb 25;7(314):ra20. doi: 10.1126/scisignal.2004786.


Intestinal crypt epithelial cells synthesize glucocorticoids, steroid hormones that protect against inflammatory bowel disease. To investigate how intestinal glucocorticoids are regulated during chronic inflammation, we induced chronic colitis in mice by exposing them to the chemical dextran sulfate sodium (DSS). We found 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. We screened 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 κB (NF-κB), which both interacted with the transcription factor NR5A2 and repressed Cyp11a1 reporter activity. This repression was relieved by expression of a dominant-negative form of c-Jun amino-terminal kinase 1 (JNK1), inhibitor of NF-κB, or by a JNK inhibitor. Furthermore, the dominant-negative TNF inhibitor XPro1595 inhibited c-Jun and NF-κB 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cholesterol Side-Chain Cleavage Enzyme / biosynthesis
  • Cholesterol Side-Chain Cleavage Enzyme / genetics
  • Cholesterol Side-Chain Cleavage Enzyme / immunology
  • Chronic Disease
  • Colitis / chemically induced
  • Colitis / genetics
  • Colitis / immunology
  • Colitis / metabolism*
  • Colitis / pathology
  • Corticosterone / biosynthesis
  • Corticosterone / genetics
  • Corticosterone / immunology
  • Dextran Sulfate / toxicity
  • Gene Expression Regulation, Enzymologic / genetics
  • Gene Expression Regulation, Enzymologic / immunology
  • Glucocorticoids / biosynthesis*
  • Glucocorticoids / genetics
  • Glucocorticoids / immunology
  • Humans
  • Intestinal Mucosa / metabolism*
  • Intestines / immunology
  • Intestines / pathology
  • Mice
  • Mitogen-Activated Protein Kinase 8 / genetics
  • Mitogen-Activated Protein Kinase 8 / immunology
  • Mitogen-Activated Protein Kinase 8 / metabolism
  • NF-kappa B / genetics
  • NF-kappa B / immunology
  • NF-kappa B / metabolism
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / immunology
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Steroid 11-beta-Hydroxylase / biosynthesis
  • Steroid 11-beta-Hydroxylase / genetics
  • Steroid 11-beta-Hydroxylase / immunology
  • Th1 Cells / immunology
  • Th1 Cells / metabolism
  • Th1 Cells / pathology
  • Th17 Cells / immunology
  • Th17 Cells / metabolism
  • Th17 Cells / pathology
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / immunology
  • Tumor Necrosis Factor-alpha / metabolism*


  • Glucocorticoids
  • NF-kappa B
  • Nr5a2 protein, mouse
  • Receptors, Cytoplasmic and Nuclear
  • Tumor Necrosis Factor-alpha
  • Dextran Sulfate
  • Steroid 11-beta-Hydroxylase
  • Cholesterol Side-Chain Cleavage Enzyme
  • Mitogen-Activated Protein Kinase 8
  • Corticosterone