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1
,
*
Department of Pediatrics, Division of Clinical Immunology, Crippled Children’s Foundation Research Center at LeBonheur Children’s Medical Center, Memphis, TN 38103;
Department of Medicine, Division of Connective Tissue Diseases, University of Tennessee, Memphis, TN 38163; and
Department of Veterans Affairs Medical Center, Memphis, TN 38104
Cultured dermal fibroblasts from systemic sclerosis patients
express higher levels of intracellular IL-1
than fibroblasts from
healthy controls. In this study, we found that systemic sclerosis
dermal fibroblasts also express higher levels of the intracellular
isoform of IL-1 receptor antagonist (icIL-1Ra) than normal fibroblasts
after stimulation with IL-1ß or TNF-. A possible relationship
between elevated precursor IL-1 (preIL-1) and elevated icIL-1Ra
was investigated by transducing normal dermal fibroblasts to
overexpress preIL-1, preIL-1ß, or icIL-1Ra. Fibroblasts that
overexpressed icIL-1Ra did not have elevated levels of IL-1. On the
other hand, fibroblasts that overexpressed preIL-1 had at least
4-fold higher basal levels of icIL-1Ra than control fibroblasts and
4-fold higher levels of icIL-1Ra after induction with IL-1ß or
TNF-. Fibroblasts overexpressing preIL-1ß did not exhibit elevated
icIL-1Ra. The differences in icIL-1Ra protein levels were reflected in
differences in mRNA. In contrast, IL-1-stimulated levels of MCP-1 and
IL-6 were not different in control and preIL-1-transduced
fibroblasts. Addition of neutralizing anti-IL-1 Abs to
fibroblast cultures did not diminish basal or stimulated levels of
icIL-1Ra in the preIL-1-transduced cells, supporting an
intracellular site of action of preIL-1. This is the first report of
an association between intracellular levels of these IL-1 family
members. We hypothesize that intracellular preIL-1 participates in
the regulation of icIL-1Ra.
This article has been cited by other articles:
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  Y. Kawaguchi, E. Nishimagi, A. Tochimoto, M. Kawamoto, Y. Katsumata, M. Soejima, T. Kanno, N. Kamatani, and M. Hara Intracellular IL-1{alpha}-binding proteins contribute to biological functions of endogenous IL-1{alpha} in systemic sclerosis fibroblasts PNAS, September 26, 2006; 103(39): 14501 - 14506. [Abstract] [Full Text] [PDF]
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 W. P Arend and C. J Guthridge Biological role of interleukin 1 receptor antagonist isoforms Ann Rheum Dis, November 1, 2000; 59(90001): i60 - 64. [Abstract] [Full Text] [PDF]
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