Intracellular IL-1 receptor antagonist is elevated in human dermal fibroblasts that overexpress intracellular precursor IL-1α

Gloria C. Higgins, Yong Wu, Arnold Postlethwaite

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Abstract

Cultured dermal fibroblasts from systemic sclerosis patients express higher levels of intracellular IL-1α 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-1β or TNF-α. A possible relationship between elevated precursor IL-1α (preIL- 1α) and elevated icIL-1Ra was investigated by transducing normal dermal fibroblasts to overexpress preIL-1α, preIL-1β, or icIL-1Ra. Fibroblasts that overexpressed icIL-1Ra did not have elevated levels of IL-1α. On the other hand, fibroblasts that overexpressed preIL-1α 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-1β or TNF-α. Fibroblasts overexpressing preIL-1β 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-1α-transduced fibroblasts. Addition of neutralizing anti- IL-1α Abs to fibroblast cultures did not diminish basal or stimulated levels of icIL-1Ra in the preIL-1α-transduced cells, supporting an intracellular site of action of preIL-1α. This is the first report of an association between intracellular levels of these IL-1 family members. We hypothesize that intracellular preIL-1α participates in the regulation of icIL-1Ra.

Original languageEnglish (US)
Pages (from-to)3969-3975
Number of pages7
JournalJournal of Immunology
Volume163
Issue number7
StatePublished - Oct 1 1999

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Interleukin-1 Receptors
Fibroblasts
Protein Isoforms
Interleukin-1
Skin
Systemic Scleroderma
interleukin 1 precursor
Interleukin-6

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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Intracellular IL-1 receptor antagonist is elevated in human dermal fibroblasts that overexpress intracellular precursor IL-1α. / Higgins, Gloria C.; Wu, Yong; Postlethwaite, Arnold.

In: Journal of Immunology, Vol. 163, No. 7, 01.10.1999, p. 3969-3975.

Research output: Contribution to journalArticle

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abstract = "Cultured dermal fibroblasts from systemic sclerosis patients express higher levels of intracellular IL-1α 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-1β or TNF-α. A possible relationship between elevated precursor IL-1α (preIL- 1α) and elevated icIL-1Ra was investigated by transducing normal dermal fibroblasts to overexpress preIL-1α, preIL-1β, or icIL-1Ra. Fibroblasts that overexpressed icIL-1Ra did not have elevated levels of IL-1α. On the other hand, fibroblasts that overexpressed preIL-1α 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-1β or TNF-α. Fibroblasts overexpressing preIL-1β 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-1α-transduced fibroblasts. Addition of neutralizing anti- IL-1α Abs to fibroblast cultures did not diminish basal or stimulated levels of icIL-1Ra in the preIL-1α-transduced cells, supporting an intracellular site of action of preIL-1α. This is the first report of an association between intracellular levels of these IL-1 family members. We hypothesize that intracellular preIL-1α participates in the regulation of icIL-1Ra.",
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