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

J Immunol. 1999 Oct 1;163(7):3969-75.

Abstract

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

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Aged
  • Cells, Cultured
  • Cytokines / biosynthesis
  • Female
  • Fibroblasts / immunology
  • Fibroblasts / metabolism*
  • Fibroblasts / pathology
  • Genetic Vectors / immunology
  • Genetic Vectors / metabolism
  • Humans
  • Immune Sera / pharmacology
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-1 / antagonists & inhibitors*
  • Interleukin-1 / biosynthesis*
  • Interleukin-1 / genetics
  • Interleukin-1 / immunology
  • Intracellular Fluid / immunology
  • Intracellular Fluid / metabolism*
  • Male
  • Middle Aged
  • Protein Precursors / antagonists & inhibitors*
  • Protein Precursors / biosynthesis*
  • Protein Precursors / genetics
  • Protein Precursors / immunology
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / metabolism
  • Receptors, Interleukin-1 / antagonists & inhibitors*
  • Retroviridae / genetics
  • Scleroderma, Systemic / immunology
  • Scleroderma, Systemic / metabolism
  • Scleroderma, Systemic / pathology
  • Sialoglycoproteins / biosynthesis
  • Sialoglycoproteins / genetics
  • Sialoglycoproteins / metabolism*
  • Skin / cytology*
  • Skin / immunology
  • Skin / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • Cytokines
  • IL1RN protein, human
  • Immune Sera
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-1
  • Protein Precursors
  • RNA, Messenger
  • Receptors, Interleukin-1
  • Sialoglycoproteins
  • Tumor Necrosis Factor-alpha
  • interleukin 1 precursor