title: Effects of a corticosteroid, budesonide, on production of bioactive IL-12 by human monocytes.
abstract: Interleukin 12 (IL-12) has a key role during the initial phase of the immune response, favouring development of T helper class 1 (Th1) cells. IL-12 is composed of two subunits, p35 and p40, which are both needed for bioactivity. The level of p35 expression determines the level of bioactive IL-12 (p70), while the p40 subunit is produced in excess. In the present study we examined the sensitivity of bioactive IL-12 production by human monocytes to a corticosteroid, budesonide. We also compared the corticosteroid sensitivity of IL-12 and two other cytokines, interleukin 1beta and granulocyte-macrophage colony-stimulating factor (GM-CSF). Monocytes obtained from peripheral blood of healthy donors (n=12) were stimulated with lipopolysaccharide (LPS; 10 microg/ml; 20 h) in the presence or absence of budesonide (10(-11)-10(-7) M). The supernatants were assayed for IL-12 (p70), IL-1beta and GM-CSF concentrations using specific immunoassays. Budesonide potently inhibited the production of bioactive IL-12. A significant suppression was obtained by treatment with even very low budesonide concentrations; even 10(-11) M budesonide significantly inhibited IL-12 to 81.6+/-7.6% of the control level (P<0.05). The maximal inhibitory effect of budesonide was seen at 10(-8) M. The inhibition of IL-12 production was significantly higher than the inhibition of GM-CSF (P<0.01) or IL-1beta (P<0.001). Whereas IL-12 production was totally inhibited, GM-CSF production was inhibited to 16.4+/-3.7 and IL-1beta production to 43.1+/-7.3% of control, respectively. The dramatic capacity of corticosteroids to modulate production of IL-12 as well as other cytokines may be a major mechanism underlying the effectiveness of these drugs in a broad spectrum of inflammatory diseases.
authors.affiliation: Department of Respiratory Medicine and Allergology, Lund University Hospital, Lund, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Larsson
authors.forename: M
authors.initials: M
authors.lastname: Linden
mesh_terms: D000287:Administration, Topical; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D019819:Budesonide / Q000494:pharmacology*; D005938:Glucocorticoids; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D007375:Interleukin-1; D008070:Lipopolysaccharides; D018664:Interleukin-12; D019819:Budesonide; D016178:Granulocyte-Macrophage Colony-Stimulating Factor