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Interleukin-1 Receptor Antagonist Ribonucleic Acid and Protein Expression by Cultured Graves’ and Normal Orbital Fibroblasts Is Differentially Modulated by Dexamethasone and Irradiation1
Ist Teil von
The journal of clinical endocrinology and metabolism, 2000-02, Vol.85 (2), p.734-742
Ort / Verlag
Endocrine Society
Erscheinungsjahr
2000
Quelle
Oxford Journals 2020 Medicine
Beschreibungen/Notizen
Recent data have indicated that orbital fibroblasts (OF) can be
stimulated to produce marked quantities of interleukin-1 receptor
antagonist (IL-1RA), a powerful inhibitor of the proinflammatory
activities of interleukin-1 in the orbital tissues in Graves’
ophthalmopathy (GO). We examined whether the beneficial effects of
dexamethasone or irradiation, the two main therapeutic modalities
applied in patients with active GO, may be related to their capacity to
alter IL-1RA ribonucleic acid (RNA) and protein expression in OF. Early
passages of cultured OF were obtained from orbital connective tissue
and extraocular muscle of patients with severe active GO and five
control subjects. Modulation of the two variants of IL-1RA,
intracellular IL-1RA (icIL-1RA) and soluble IL-1RA (sIL-1RA), was
studied after exposure of OF to increasing concentrations of
dexamethasone (10−10-10−6 mol/L), the
glucocorticoid receptor antagonist RU 38486 (10−3 mol/L),
or combinations thereof. Alternatively, cell monolayers were exposed to
increasing doses of UV irradiation (0.1–1 J/cm2) or
ionizing irradiation (0.2–2 Gy). The IL-1RA gene and protein variants
were analyzed by RT-PCR, immunocytochemistry, immunoblotting, and
enzyme-linked immunosorbent assay. Dexamethasone inhibited IL-1RA RNA
steady state levels in GO OF and control OF in a dose-dependent manner.
Combined exposure of OF to dexamethasone and RU 38486 completely
restored baseline levels of IL-1RA RNA. By contrast, low doses of UV
and ionizing irradiation dose dependently up-regulated IL-1RA-specific
transcripts in GO OF and control OF, whereas higher doses were less
effective. Immunoblotting and enzyme-linked immunosorbent assay
revealed suppression of IL-1RA immunoreactivity after treatment with
dexamethasone and enhanced expression of IL-1RA by GO OF and normal OF
after low doses of UV and ionizing irradiation. Our results indicate
that, in contrast to dexamethasone, low doses of irradiation stimulate
expression of the IL-1RA gene and protein variants in OF. Induction by
irradiation of IL-1RA expression in target cells of the orbital immune
process represents an as yet unrecognized mechanism by which orbital
radiotherapy may exert some of its beneficial therapeutic effects in
patients with active GO.