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IB Kinase Is Critical for TNF--Induced VCAM1 Gene Expression in Renal Tubular Epithelial Cells¹

Zheng Tu^*, Vicki Rubin Kelley, Tucker Collins and Frank S. Lee^2,*

^* Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; and Laboratory of Molecular Autoimmune Disease, Renal Division, Department of Medicine, and Vascular Research Division, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115

The expression of VCAM1 is up-regulated in renal proximal tubular epithelial cells (TEC) in a variety of inflammatory renal diseases, a prominent example of which is acute renal allograft rejection. VCAM1 may play an important role in these diseases because it binds to the integrins very late Ag-4 and ₄₇ on lymphocytes and monocytes, thereby providing a potential mechanism to recruit these leukocytes to sites of inflammation. The molecular mechanisms underlying VCAM1 regulation in renal TEC are essentially unknown. We now report that VCAM1 mRNA is dramatically up-regulated in C1, a cell line derived from renal TEC, on exposure to TNF-. Two NF-B binding sites in the VCAM1 promoter are critical for the TNF--induced VCAM1 transcriptional up-regulation, and both sites bind to p65-p50 NF-B complexes. TNF- induces activation of inhibitor of NF-B (IB) kinase- (IKK-), a protein kinase that phosphorylates the NF-B inhibitor IB, and thereby targets the latter for degradation via the ubiquitin-proteasome pathway. Moreover, dominant negative versions of IKK inhibit TNF- activation of a VCAM1 promoter reporter. We conclude that the IKK/NF-B pathway is critical in the TNF--induced up-regulation of VCAM1 mRNA in renal TEC.

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