IL-2 and IL-4 counteract budesonide inhibition of GM-CSF and IL-10, but not of IL-8, IL-12 or TNF-alpha production by human mononuclear blood cells.
1. The combination of interleukin-2 (IL-2) and IL-4 reduces the inhibitory effects of glucocorticoids on granulocyte-macrophage colony-stimulating factor (GM-CSF) production, in agreement with the hypothesis that this combination causes glucocorticoid resistance. Whether a general cytokine resistance to glucocorticoids is induced by IL-2 and IL-4 has not been reported. 2. Mononuclear blood cells from healthy individuals were pre-treated with IL-2, IL-4, or IL-2+ IL-4 (31.3-500 U ml(-1)) for 48 h, prior to lipopolysaccharide (LPS; 10 ng ml(-1); 20 h) and budesonide addition. Cytokine levels in the supernatants were analysed using specific immunoassays. DNA content was analysed to estimate cell numbers. 3. GM-CSF production was totally inhibited by budesonide at 10(-8) M in vehicle treated cultures, while IL-10 was inhibited to 33.4+/-4.3% of control. IL-2, IL-4, or IL-2 + IL-4 reduced the inhibitory effects of budesonide on GM-CSF to similar levels (23.7 6.7, 31.6+/-8.5 and 35.1+/-4.3% of control, respectively). IL-2, IL-4, or IL-2 + IL-4 also reduced the inhibitory effects of budesonide on IL-10 production (46.5+/-6.6, 55.9+/-7.3%, and 68.3+/-9.9% of control, respectively). In contrast, IL-8, IL-12 and TNF-alpha production did not become resistant to budesonide. 4. Thus, glucocorticoid resistance induced by IL-2 and IL-4 is not general at the cytokine production level. While the glucocorticoid sensitivity of GM-CSF and IL-10 production decreased, the sensitivity of IL-8, IL-12 or TNF-alpha production was unchanged. Also, the mixture of IL-2 and IL-4 is not crucial for induction of glucocorticoid resistance of GM-CSF production.
Larsson
S
S
Department of Respiratory Medicine, Lund University Hospital, Sweden.
Löfdahl
C G
CG
Linden
M
M
D019819:Budesonide / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D004351:Drug Resistance; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors*; D006801:Humans; D016753:Interleukin-10 / Q000037:antagonists & inhibitors*; D018664:Interleukin-12 / Q000096:biosynthesis; D007376:Interleukin-2 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology*; D016209:Interleukin-8 / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D016207:Cytokines; D007376:Interleukin-2; D016209:Interleukin-8; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D018664:Interleukin-12; D015847:Interleukin-4; D019819:Budesonide; D016178:Granulocyte-Macrophage Colony-Stimulating Factor