CYTOKINE-INDUCED INTERLEUKIN-1 RECEPTOR ANTAGONIST RELEASE IN MONONUCLEAR PHAGOCYTES

IL-1ra has recently been shown to suppress both cytokine- and endotoxin-induced IL-1beta and TNF-alpha release from monocytes. Given that mononuclear phagocytes can produce both the proinflammatory cytokines IL-1alpha, IL-1beta, and TNF-alpha as well as the suppressive cytokine IL-1ra, we proposed that IL-1alpha, IL-1beta, and TNF-alpha may induce IL-1ra from mononuclear phagocytes. To test this hypothesis, human mononuclear cells were stimulated for 18 h with IL-1alpha, IL-1beta, or TNF-alpha, and the supernatants assayed for IL-1ra by ELISA. Each cytokine induced IL-1ra secretion in a dose-response manner. However, IL-1alpha and IL-1beta were better inducers of IL-1ra than was TNF-alpha. IL-1alpha or IL-1beta at a dose of 10 ng/ml induced 3 to 6 ng/ml of IL-1ra, while TNF-alpha at a dose of 100 ng/ml stimulated only 1.4 ng/ml of IL-1ra. This induction was not due to endotoxin, as all cytokines contained less than 10 pg/ml of contaminating LPS. Furthermore, for IL-1beta-induced IL-1ra, immunoprecipitation of IL-1beta with an anti-IL-1beta antibody, but not a preimmune antibody, blocked the induction of IL-1ra. In contrast to mononuclear phagocytes, IL-1alpha, IL-1beta, and TNF-alpha did not induce further IL-1ra production in alveolar macrophages. This lack of macrophage responsiveness may relate to the constitutive production of IL-1ra by these mature mononuclear phagocytes. Together, these findings suggest that IL-1alpha, IL-1beta, and TNF-alpha from blood mononuclear cells may induce negative feedback on proinflammatory cytokine production by up-regulating IL-1ra.