In vitro pretreatment of human mononuclear blood cells with a combination of interleukin-2 and interleukin-4 decreases corticosteroid receptor affinity and reduces the anti-proliferative effects of corticosteroids. Similar abnormalities have been observed in mononuclear blood cells of steroid-resistant asthmatics. In vitro steroid resistance was induced by 48 h pretreatment of mononuclear blood cells from healthy individuals (n = 10) with interleukin-2 and interleukin-4 (500 Units (U)/ml). The effects of three structurally different corticosteroids (10(-7)-10(-11) M) on lipopolysaccharide-stimulated (10 ng/ml; 20 h) production of granulocyte-macrophage colony-stimulating factor (GM-CSF) were examined. GM-CSF production was efficiently inhibited by all three corticosteroids in the control cultures. Cortivazol was significantly more potent (IC50 = 3 x 10(-11) M) than budesonide and tipredane (IC50 = 2.5 x 10(-10) M and IC50 = 2 x 10(-10) M, respectively). However. interleukin-2 and interleukin-4 pretreatment counteracted the inhibitory effects of all three corticosteroids to a similar degree. The results highlight the importance of interleukin-2 and interleukin-4 in the induction of steroid resistance, since pretreatment of mononuclear blood cells with these cytokines impaired corticosteroid inhibition of GM-CSF production.