A nuclear target for interleukin-1α: Interaction with the growth suppressor necdin modulates proliferation and collagen expression

Bo Hu, Shuhui Wang, Yingze Zhang, Carol A. Feghali, Jeffrey R. Dingman, Timothy M. Wright*

*Corresponding author for this work

Research output: Contribution to journalArticle

51 Scopus citations

Abstract

There is growing evidence for the intracellular role of cytokines and growth factors, but the pathways by which these activities occur remain largely obscure. Previous work from our laboratory identified the constitutive, aberrant expression of the 31-kDa IL-1α precursor (pre-IL-1α) in the nuclei of fibroblasts from the lesional skin of patients with systemic sclerosis (SSc). We established that pre-IL-1α expression was associated with increased fibroblast proliferation and collagen production. Further investigation has led to the identification of a mechanism by which nuclear expression of pre-IL-1α affects fibroblast growth and matrix production. By using a yeast two-hybrid method, we found that pre-IL-1α binds necdin, a nuclear protein with growth suppressor activity. We mapped the region of pre-IL-1α responsible for necdin binding and found it to be localized near the N terminus, a region that is present on pre-IL-1α, but not the mature 17-kDa cytokine. Expression studies demonstrated that pre-IL-1α associates with necdin in the nuclei of mammalian cell lines and regulates cell growth and collagen expression. Our results provide the first evidence, to our knowledge, of a nuclear target for pre-IL-1α. Based on these findings, we propose that the constitutively up-regulated expression of pre-IL-1α in the nuclei of SSc fibroblasts up-regulates proliferation and matrix production of SSc fibroblasts through binding necdin, and by counteracting its effects on cell growth and collagen production.

Original languageEnglish (US)
Pages (from-to)10008-10013
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number17
DOIs
StatePublished - Aug 19 2003

ASJC Scopus subject areas

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