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.