Interleukin-2 and -4 induce resistance of granulocyte-macrophage colony-stimulating factor to corticosteroids.
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.
Larsson
S
S
Department of Respiratory Medicine and Allergology, Lund University Hospital, Sweden.
Brattsand
R
R
Linden
M
M
D000730:Androstadienes / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D019819:Budesonide / Q000494:pharmacology; D002478:Cells, Cultured; D004351:Drug Resistance; D004357:Drug Synergism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors*; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology* / Q000502:physiology; D015847:Interleukin-4 / Q000494:pharmacology* / Q000502:physiology; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000502:physiology; D011281:Pregnatrienes / Q000494:pharmacology
D000730:Androstadienes; D000893:Anti-Inflammatory Agents; D007376:Interleukin-2; D011281:Pregnatrienes; C051756:tipredane; D015847:Interleukin-4; D019819:Budesonide; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C005924:cortivazol