Intracellular IL-1alpha-binding proteins contribute to biological functions of endogenous IL-1alpha in systemic sclerosis fibroblasts.
The aberrant production of precursor IL-1alpha (pre-IL-1alpha) 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-1alpha regulates the expression of the other molecules in fibroblasts. We report here that pre-IL-1alpha can form a complex with IL-1alpha-binding proteins that is translocated into the nuclei of fibroblasts. Immunoprecipitation that used anti-human IL-1alpha Ab and (35)S-labeled nuclear extracts of fibroblasts showed three specific bands (approximately equal to 31, 35, and 65 kDa). The 31-kDa molecule was identified as pre-IL-1alpha, and the 35- and 65-kDa molecules might be pre-IL-1alpha-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 II (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-1alpha was not translocated into the nucleus by an inhibition of HAX-1. These findings reveal that nuclear localization of pre-IL-1alpha 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.
Kawaguchi
Yasushi
Y
Institute of Rheumatology, Tokyo Women's Medical University, 10-22 Kawada-cho, Shinjuku-ku, Tokyo 162-0054, Japan. y-kawa@ior.twmu.ac.jp
Nishimagi
Emi
E
Tochimoto
Akiko
A
Kawamoto
Manabu
M
Katsumata
Yasuhiro
Y
Soejima
Makoto
M
Kanno
Tokiko
T
Kamatani
Naoyuki
N
Hara
Masako
M
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000473:pathology*; D005786:Gene Expression Regulation; D006801:Humans; D047468:Immunoprecipitation; D007375:Interleukin-1 / Q000378:metabolism*; D051379:Mice; D008875:Middle Aged; D008954:Models, Biological; D041681:NIH 3T3 Cells; D011485:Protein Binding; D011498:Protein Precursors / Q000378:metabolism; D021381:Protein Transport; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D053574:Receptors, Interleukin-1 Type II; D012595:Scleroderma, Systemic / Q000473:pathology*; D015398:Signal Transduction; D020798:Two-Hybrid System Techniques
D048868:Adaptor Proteins, Signal Transducing; D024042:Collagen Type I; C104759:HAX1 protein, human; D007375:Interleukin-1; D011498:Protein Precursors; D011506:Proteins; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; D053574:Receptors, Interleukin-1 Type II