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

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-1alpha precursor (pre-IL-1alpha) in the nuclei of fibroblasts from the lesional skin of patients with systemic sclerosis (SSc). We established that pre-IL-1alpha 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-la affects fibroblast growth and matrix production. By using a yeast two-hybrid method, we found that pre-IL-1alpha binds necdin, a nuclear protein with growth suppressor activity. We mapped the region of pre-IL-la responsible for necdin binding and found it to be localized near the N terminus, a region that is present on pre-IL-1alpha, but not the mature 17-kDa cytokine. Expression studies demonstrated that pre-IL-1alpha 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-1alpha. Based on these findings, we propose that the constitutively up-regulated expression of pre-IL-1alpha 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.