Critical role of NF-kappaB and stress-activated protein kinases in steroid unresponsiveness

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Updated: Sep 29, 2026

A Guide to Production, Crystallization, and Structure Determination of Human IKK1/α
11:27

A Guide to Production, Crystallization, and Structure Determination of Human IKK1/α

Published on: November 2, 2018

Heike Bantel1, M Lienhard Schmitz, Armin Raible

  • 1Institute of Molecular Medicine, University of Düsseldorf, Germany.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|September 12, 2002
PubMed

Insights

Glucocorticoid resistance in Crohn's disease is linked to inflammation mediators like NF-kappaB and JNK. In resistant patients, these are activated in epithelial cells, unlike sensitive patients where they activate in macrophages.

Area of Science:

  • Immunology
  • Molecular Biology
  • Gastroenterology

Background:

  • Glucocorticoid resistance is a significant clinical challenge in chronic inflammatory diseases.
  • Patients with rheumatoid arthritis, asthma, and Crohn's disease often do not respond to steroid therapy.
  • The underlying molecular mechanisms of glucocorticoid unresponsiveness remain largely unknown.

Purpose of the Study:

  • To investigate the activation patterns of key inflammatory mediators in steroid-sensitive versus steroid-resistant Crohn's disease patients.
  • To explore the role of nuclear factor-kappaB (NF-kappaB), activator protein-1 (AP-1), p38, and c-Jun N-terminal kinase (JNK) in glucocorticoid resistance.
  • To elucidate how these mediators interfere with the glucocorticoid receptor (GR) function.

Main Methods:

  • Comparative analysis of transcription factor and kinase activation in immune and epithelial cells from Crohn's disease patients.
  • Utilized reporter gene assays to assess the functional interference of inflammatory mediators with GR activity.
  • Examined the activation of NF-kappaB, AP-1, p38, and JNK in lamina propria macrophages and epithelial cells.

Main Results:

  • Steroid-sensitive Crohn's disease patients showed activation of NF-kappaB, AP-1, p38, and JNK primarily in lamina propria macrophages.
  • Steroid-resistant Crohn's disease patients exhibited activation of these mediators predominantly in epithelial cells.
  • Reporter gene assays confirmed that NF-kappaB, JNK1, and p38 expression can inhibit GR activity.

Conclusions:

  • Steroid resistance in Crohn's disease is associated with heightened epithelial cell activation of stress-activated protein kinases and NF-kappaB.
  • This increased epithelial activation may suppress the anti-inflammatory effects of the glucocorticoid receptor.
  • Findings suggest novel therapeutic targets for overcoming glucocorticoid resistance in inflammatory conditions.

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