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NF-B Mediated IL-6 Production by Renal Epithelial Cells Is Regulated by C-Jun NH₂-Terminal Kinase

Simone de Haij^*, Astrid C. Bakker^*, Reinier N. van der Geest^*, Guy Haegeman, Wim Vanden Berghe, Jamil Aarbiou, Mohamed R. Daha^* and Cees van Kooten^*

^* Department of Nephrology; Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands; and Department of Molecular Biology, LEGEST, University of Gent, Gent, Belgium

Address correspondence to: Dr. Cees van Kooten, Department of Nephrology, Leiden University Medical Center, Building 1, C3P, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. Phone: +31-71-526-3964; Fax: +31-71-526-6868; E-mail: kooten{at}lumc.nl

Received for publication September 20, 2004. Accepted for publication March 7, 2005.

Tubular epithelial cells (TEC) play an important role in tubulointerstitial inflammation, a hallmark of most renal diseases, via production of cytokines and chemokines. In this study, the role of mitogen-activated protein kinases (MAPK) in regulation of the proinflammatory cytokine IL-6 in cultured human TEC in response to the leukocyte-derived factors IL-1, TNF-, IL-17, and CD40L was investigated. IL-6 production induced by IL-1, TNF-, and IL-17 was specifically inhibited by the c-jun NH₂-terminal kinase (JNK) inhibitor SP600125, but not by a selective inhibitor of p38 MAPK, and was moderately increased when the ERK1/2 pathway was inhibited. Also for CD40L stimulation, inhibition of JNK resulted in a pronounced inhibition of IL-6 production. Although stimulation of TEC induced activation of activator protein–1 (AP-1), the down-stream target of JNK, reporter assays demonstrated that mutation of the AP-1 binding site in the IL-6 promoter did not affect gene transcription. Furthermore, IL-1–induced transcriptional activation of the IL-6 promotor was repressed by SP600125 or by co-transfection of a dominant-negative expression plasmid of c-jun even in the absence of a functional AP-1 binding site. This suggests that IL-6 production by renal epithelial cells is regulated by JNK, via a mechanism, however, independent of the AP-1 binding site. The data rather suggest that the JNK pathway may interfere with other signaling pathways, involving NF-B and possibly ERK.

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