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Molecular and Cellular Biology, November 1999, p. 7688-7696, Vol. 19, No. 11
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

RelB Modulation of Ikappa Balpha Stability as a Mechanism of Transcription Suppression of Interleukin-1alpha (IL-1alpha ), IL-1beta , and Tumor Necrosis Factor Alpha in Fibroblastsdagger

Yiyang Xia,1 Shizhong Chen,1 Yibin Wang,2 Nigel Mackman,1 George Ku,3 David Lo,1 and Lili Feng1,*

Department of Immunology, The Scripps Research Institute, La Jolla, California 920371; Department of Medicine, University of California, San Diego, La Jolla, California 920932; and Vertex Pharmaceuticals Inc., Cambridge, Massachusetts 021393

Received 3 March 1999/Returned for modification 8 April 1999/Accepted 10 August 1999

Members of the NF-kappa B/RelB family of transcription factors play important roles in the regulation of inflammatory and immune responses. RelB, a member of this family, has been characterized as a transcription activator and is involved in the constitutive NF-kappa B activity in lymphoid tissues. However, in a previous study we observed an overexpression of chemokines in RelB-deficient fibroblasts. Here we show that RelB is an important transcription suppressor in fibroblasts which limits the expression of proinflammatory mediators and may exert its function by modulating the stability of Ikappa Balpha protein. Fibroblasts from relb-/- mice overexpress interleukin-1alpha (IL-1alpha ), IL-1beta , and tumor necrosis factor alpha in response to lipopolysaccharide (LPS) stimulation. These cells have an augmented and prolonged LPS-inducible IKK activity and an accelerated degradation which results in a diminished level of Ikappa Balpha protein, despite an upregulated Ikappa Balpha mRNA expression. Consequently, NF-kappa B activity was augmented and postinduction repression of NF-kappa B activity was impaired in these cells. The increased kappa B-binding activity and cytokine overexpression was suppressed by introducing RelB cDNA or a dominant negative Ikappa Balpha into relb-/- fibroblasts. Our findings suggest a novel transcription suppression function of RelB in fibroblasts.

* Corresponding author. Mailing address: Department of Immunology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037. Phone: (858) 784-8262. Fax: (858) 784-8558. E-mail: llfimm{at}scripps.edu.

dagger Publication 12172-IMM from the Department of Immunology, The Scripps Research Institute, La Jolla, Calif.

Molecular and Cellular Biology, November 1999, p. 7688-7696, Vol. 19, No. 11
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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