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Intracellular IL-1 Receptor Antagonist Is Elevated in Human Dermal Fibroblasts That Overexpress Intracellular Precursor IL-1¹

Gloria C. Higgins^2,*, Yong Wu and Arnold E. Postlethwaite^,

^* 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.