IFNs are critical regulators of IL-1 receptor antagonist and IL-1 expression in human microglia.
Because IL-1 is implicated in the pathogenesis of multiple sclerosis, and IFNs are known to alter disease course, we sought to determine whether IFNs can regulate the expression of IL-1 and IL-1R antagonist (IL-1Ra) in primary cultures of human microglia and astrocytes. We found that IL-1 and IL-1Ra are products of microglia but not astrocytes, and IFN-beta and IFN-gamma differentially modulate LPS- and cytokine-induced IL-1 and IL-1Ra. IFN-beta induces IL-1Ra and augments LPS- and IL-4-induced IL-1Ra, but suppresses LPS- and IL-1-induced IL-1, shifting the balance toward the expression of the IL-1Ra. Like IFN-beta, IFN-gamma suppresses the expression of both LPS and IL-1-induced IL-1beta. However, IFN-gamma also suppresses the expression of IFN-beta- and IL-4-induced IL-1Ra so that IFN-gamma may enhance or suppress IL-1 activity depending on the other cytokines present. IL-4 has similar effects to IFN-beta; however, other anti-inflammatory cytokines, did not regulate IL-1 or IL-1Ra in human microglia. Our data demonstrate a novel suppressive effect of IFN-beta and IL-4 on IL-1 activity in human microglia, suggesting that IFN-beta, a therapeutic agent used for multiple sclerosis, could have wider applications in the treatment of other central nervous system disorders in which IL-1 activity has been implicated in the pathogenesis.
Department of Pathology (Neuropathology), Albert Einstein College of Medicine, Bronx, NY 10461, USA.
J S
JS
Liu
T D
TD
Amaral
C F
CF
Brosnan
S C
SC
Lee
D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D005333:Fetus; D006801:Humans; D016899:Interferon-beta / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology*; D053590:Interleukin 1 Receptor Antagonist Protein; D016753:Interleukin-10 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D012795:Sialoglycoproteins / Q000096:biosynthesis* / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D015850:Interleukin-6; D017472:Receptors, Interleukin-1; D012795:Sialoglycoproteins; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D015847:Interleukin-4; D016899:Interferon-beta; D007371:Interferon-gamma