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NF-kappaB mediated IL-6 production by renal epithelial cells is regulated by c-jun NH2-terminal kinase

Simone de Haij1, Astrid C Bakker, Reinier N van der Geest

  • 1Department of Nephrology, Leiden University Medical Center, Building 1, C3P, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.

Journal of the American Society of Nephrology : JASN
|April 22, 2005
PubMed

Insights

The c-jun NH(2)-terminal kinase (JNK) pathway regulates interleukin-6 (IL-6) production in kidney cells. This regulation occurs independently of the activator protein-1 (AP-1) binding site, suggesting complex signaling interactions.

Area of Science:

  • Renal cell biology
  • Molecular immunology
  • Inflammation signaling pathways

Background:

  • Tubular epithelial cells (TECs) are key mediators of tubulointerstitial inflammation in kidney diseases.
  • Cytokine and chemokine production by TECs contributes significantly to renal pathology.
  • Mitogen-activated protein kinases (MAPKs) are critical regulators of cellular responses, including inflammation.

Purpose of the Study:

  • To investigate the role of MAPK pathways in regulating the proinflammatory cytokine IL-6 production in human TECs.
  • To determine how leukocyte-derived factors (IL-1, TNF-alpha, IL-17, CD40L) influence IL-6 production via MAPK signaling.
  • To elucidate the specific MAPK pathways involved in IL-6 gene regulation in TECs.

Main Methods:

  • Primary human TEC culture.
  • Stimulation with IL-1, TNF-alpha, IL-17, and CD40L.
  • Pharmacological inhibition of JNK (SP600125) and p38 MAPK.
  • Analysis of IL-6 production via ELISA or similar assays.
  • Reporter assays to assess IL-6 promoter activity.
  • Western blotting to detect signaling pathway activation (e.g., AP-1).

Main Results:

  • IL-6 production induced by IL-1, TNF-alpha, and IL-17 was significantly inhibited by a JNK inhibitor (SP600125).
  • p38 MAPK inhibition did not affect IL-6 production, while ERK1/2 inhibition moderately increased it.
  • CD40L stimulation also led to pronounced IL-6 inhibition upon JNK blockade.
  • Reporter assays indicated that JNK-mediated IL-6 regulation was independent of the AP-1 binding site in the IL-6 promoter.
  • IL-1-induced IL-6 transcription was repressed by JNK inhibition or dominant-negative c-jun, even without a functional AP-1 site.

Conclusions:

  • The JNK pathway plays a crucial role in regulating IL-6 production by human TECs in response to inflammatory stimuli.
  • JNK-mediated regulation of IL-6 occurs through a mechanism independent of the canonical AP-1 binding site.
  • These findings suggest that JNK may interact with other signaling pathways, such as NF-kappaB and ERK, to control IL-6 expression in renal epithelial cells.

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