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Induction of circulating IL-1 receptor antagonist by IFN treatment
1Department of Medicine, New England Medical Center Hospitals, Boston, MA 02111.
Abstract:
This study was undertaken to determine whether IFN induce IL-1 receptor antagonist (IL-1Ra), a specific inhibitor of IL-1. Plasma samples were obtained from healthy volunteers (n = 5) and patients with chronic hepatitis C (n = 5) treated with IFN-alpha, and from patients with renal cell carcinoma (n = 6) treated with IFN-gamma and assayed for IL-1Ra by a specific radioimmunoassay. Both types of IFN were administered subcutaneously. In vitro studies were carried out with PBMC from healthy volunteers. A single, low and nontoxic dose (1 x 10(6) U) of IFN-alpha induced circulating IL-1Ra, which reached peak levels within 12 h. This effect was dose-dependent and more pronounced with a higher dose (5 x 10(6) U). Peak IL-1Ra levels 12 h after 5 x 10(6) U IFN-alpha were 4.16 +/- 0.35 ng/ml in healthy volunteers and 5.7 +/- 0.73 ng/ml in patients with chronic hepatitis C (difference not significant). Thereafter levels declined but remained elevated for 24 h. IFN-gamma treatment led only to a modest increase of circulating IL-1Ra even at a dose of 400 micrograms; this dose, however, was associated with side effects similar to those seen after injection of 5 x 10(6) U IFN-alpha. PBMC stimulated with IFN-alpha or IFN-gamma produced IL-1Ra in vitro. The induction of IL-1Ra may contribute to the antiviral, anti-inflammatory, and antiproliferative effects of IFN.
Insights
Interferon-alpha (IFN-alpha) and Interferon-gamma (IFN-gamma) induce interleukin-1 receptor antagonist (IL-1Ra) in humans and in vitro. This induction may explain some of the therapeutic effects of interferons.
Area of Science:
- Immunology
- Virology
- Oncology
Background:
- Interferons (IFNs) are cytokines with diverse biological activities.
- Interleukin-1 (IL-1) is a pro-inflammatory cytokine.
- Interleukin-1 receptor antagonist (IL-1Ra) specifically inhibits IL-1 activity.
Purpose of the Study:
- To investigate whether IFNs induce IL-1Ra production.
- To compare the effects of IFN-alpha and IFN-gamma on IL-1Ra levels.
Main Methods:
- Plasma samples from healthy volunteers and patients treated with IFN-alpha or IFN-gamma were analyzed for IL-1Ra.
- In vitro studies using peripheral blood mononuclear cells (PBMC) stimulated with IFNs were performed.
- IL-1Ra was quantified using radioimmunoassay.
Main Results:
- IFN-alpha administration induced a dose-dependent increase in circulating IL-1Ra in both healthy volunteers and patients with chronic hepatitis C.
- Peak IL-1Ra levels were observed within 12 hours post-IFN-alpha administration.
- IFN-gamma induced only a modest increase in IL-1Ra.
- Both IFN-alpha and IFN-gamma stimulated IL-1Ra production by PBMC in vitro.
Conclusions:
- IFN-alpha effectively induces IL-1Ra in vivo and in vitro.
- The induction of IL-1Ra by IFNs may contribute to their antiviral, anti-inflammatory, and antiproliferative effects.