Intracellular IL-1α-binding proteins contribute to biological functions of endogenous IL-1α in systemic sclerosis fibroblasts

The aberrant production of precursor IL-1 alpha (pre-IL-1 alpha) in skin fibroblasts that are derived from systemic sclerosis (SSc) is associated with the induction of IL-6 and procollagen, which contributes to the fibrosis of SSc. However, little is understood about how intracellular pre-IL-1 alpha regulates the expression of the other molecules in fibroblasts. We report here that pre-IL-1 alpha can form a complex with IL-1 alpha-binding proteins that is translocated into the nuclei of fibroblasts. Immunoprecipitation that used anti-human IL-1a Ab and S-35-labeled nuclear extracts of fibroblasts showed three specific bands (approximate to 31, 35, and 65 kDa). The 31-kDa molecule was identified as pre-IL-1 alpha, and the 35- and 65-kDa molecules might be pre-IL-1 alpha-binding proteins. A partial sequencing for the 10 aa from the N-terminals of the molecules showed 100% homology for HAX-1 (HS1-associated protein X-1) and IL-1 receptor type 11 (IL-1RII). Suppression of the genes of HAX-1 or IL-1RII induced the inhibitory effects of IL-1 signal transduction, including production of IL-6 and procollagen, by fibroblasts. In particular, pre-IL-1 alpha was not translocated into the nucleus by an inhibition of HAX-1. These findings reveal that nuclear localization of pre-IL-1 alpha depends on the binding to HAX-1 and that biological activities might be elicited by the binding to both HAX-1 and IL-1RII in SSc fibroblasts.