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© The Rockefeller University Press, 0021-9525/1998//709 $5.00
The Journal of Cell Biology, Volume 140, Number 3, , 1998 709-719

Article

A Three-dimensional Collagen Lattice Activates NF-{kappa}B in Human Fibroblasts: Role in Integrin {alpha}2 Gene Expression and Tissue Remodeling



Jiahua Xu*, Mary M. Zutter{ddagger}, Samuel A. Santoro{ddagger}, and Richard A.F. Clark*

* Department of Dermatology, School of Medicine, State University of New York, Stony Brook, New York 11794-8165; and {ddagger} Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110

Normal adult human dermal fibroblasts grown in a three-dimensional collagen lattice increase mRNA level of collagen receptor integrin subunit {alpha}2 (Xu, J., and R.A.F. Clark. 1996. J. Cell Biol. 132:239– 249.) and DNA binding activity of a nuclear transcription factor, NF-{kappa}B (Xu, J., and R.A.F. Clark. 1997. J. Cell Biol. 136:473–483.). Here we present evidence that the collagen lattice induced the nuclear translocation of p50, one member of NF-{kappa}B family, and the degradation of an NF-{kappa}B inhibitor protein, I{kappa}B-{alpha}. The inhibition of NF-{kappa}B activity by SN50, a peptide inhibitor targeted at nuclear translocation of NF-{kappa}B, significantly reduced the induction of integrin {alpha}2 mRNA and protein by the collagen lattice. A region located between –549 and –351 bp in the promoter of integrin {alpha}2 gene conferred the inducibility by three-dimensional collagen lattice. The presence of either SN50 or I{kappa}B-{alpha}32, 36, a stable mutant of I{kappa}B-{alpha}, abrogated this inducibility, indicating that the activation of integrin {alpha}2 gene expression was possibly mediated by NF-{kappa}B through this region. Although there were three DNA–protein binding complexes forming in this region that are sensitive to the inhibition of NF-{kappa}B nuclear translocation, NF-{kappa}B was not directly present in the binding complexes. Therefore, an indirect regulatory mechanism by NF-{kappa}B in integrin {alpha}2 gene expression induced by three-dimensional collagen lattice is suggested. The involvement of NF-{kappa}B in reorganization and contraction of three-dimensional collagen lattice, a process that requires the presence of abundant integrin {alpha}2β1, was also examined. The inhibition of NF-{kappa}B activity by SN50 greatly blocked the contraction, suggesting its critical role in not only the induction of integrin {alpha}2 gene expression by three- dimensional collagen lattice, but also {alpha}2β1-mediated tissue-remodeling process.

Abbreviations used in this paper: BIM, bisindolylmaleimide GF 109203X; COL, collagen lattice; ECM, extracellular matrix; I{kappa}B, inhibitor for NF-{kappa}B; IL, interleukin; MMP-1, type I matrix metalloproteinase; NF-{kappa}B, nuclear factor {kappa}B; PKC, protein kinase C; 3D, three-dimensional; TGF-β, transforming growth factor-β; TNF, tumor necrosis factor.

Funding for this work was provided by National Institutes of Health grant AG10114309 (R.A.F. Clark). J. Xu was supported by funding from the Dermatology Foundation and the School of Medicine, SUNY at Stony Brook.

Address all correspondence to Jiahua Xu, Department of Dermatology, School of Medicine, State University of New York, Stony Brook, New York 11794-8165. Tel.: (516) 444-3843. Fax: (516) 444-3844. E-mail: JXu{at}epo.som.sunysb.edu


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