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J. Cell Biol., Volume 140, Number 3, February 9, 1998 709-719

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,Dagger Samuel A. Santoro,Dagger and Richard A.F. Clark*

* Department of Dermatology, School of Medicine, State University of New York, Stony Brook, New York 11794-8165; and Dagger  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, Ikappa 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 Ikappa B-alpha 32, 36, a stable mutant of Ikappa 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 2beta 1, 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 2beta 1-mediated tissue-remodeling process.


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