The Th1 and Th2 cytokines IFN-gamma and IL-4 antagonize the inhibition of monocyte IL-1 receptor antagonist by glucocorticoids: involvement of IL-1.
Monocytes express IL-1 and IL-1 receptor antagonist (IL-1Ra) in response to lipopolysaccharide (LPS). IL-1 self-induction contributes to the increase in IL-1 following LPS stimulation. LPS-stimulated IL-1 and IL-1Ra production are inhibited by glucocorticoids. In the present work we examined the regulation of IL-1Ra by Th1 cytokine IFN-gamma, Th2 cytokine IL-4, glucocorticoids and IL-1 in human monocytes. We demonstrate that IL-1 contributes to LPS-induced IL-1 Ra expression as shown by IL-1 blockade in LPS-stimulated monocytes using a specific anti-IL-1beta antibody or recombinant IL-1Ra. Glucocorticoids inhibited IL-1beta-stimulated IL-1Ra mRNA expression and protein production. Glucocorticoids inhibited both IL-1-mediated and non-mediated LPS stimulation of IL-1Ra expression. Both IFN-gamma and IL-4 reversed the inhibitory effect of glucocorticoids on IL-1Ra expression and secretion. The effect of IFN-gamma was blocked by pretreatment of monocytes with an anti-IL-1beta blocking antibody, whereas the effect of IL-4 could not be blocked, demonstrating that IFN-gamma acts through a mechanism dependent on endogenous IL-1 production, whereas IL-4 acts through an IL-1-independent one. Consistent with this finding, IFN-gamma (but not IL-4) failed to reverse the inhibitory effect of glucocorticoids when stimulated by IL-1, and only IL-4 combined with IL-1 showed synergism resulting in an increase in IL-1 Ra production. The differential regulation and involvement of IL-1 in the expression of IL-1Ra by IFN-gamma, IL-4 and glucocorticoids sets the level of monocyte responsiveness during the Th1 or Th2 responses.
Kovalovsky
D
D
Departamento de Biología, FCEN, Universidad de Buenos Aires, Argentina.
Páez Pereda
M
M
Sauer
J
J
Perez Castro
C
C
Nahmod
V E
VE
Stalla
G K
GK
Holsboer
F
F
Arzt
E
E
D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000502:physiology*; D015847:Interleukin-4 / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects*; D012333:RNA, Messenger / Q000032:analysis; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors*; D012795:Sialoglycoproteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
D005938:Glucocorticoids; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; D012795:Sialoglycoproteins; D015847:Interleukin-4; D007371:Interferon-gamma