Role of interferon regulatory factor-1 in the regulation of IL-18 production and activity.
Interferon regulatory factor-1 (IRF-1) is a transcription factor regulating the expression of several cytokines. Using IRF-1 knockout (KO) mice, the role of IRF-1 in the production and activity of IL-18 was evaluated. Administration of IL-12 or concanavalin A significantly increased levels of circulating IL-18 in wild-type (WT), but not in IRF-1 KO mice. However, despite these differences in circulating IL-18 levels, no or only minor differences in constitutive or inducible IL-18 mRNA and tissue-associated protein levels were observed between WT and IRF-1 KO mice. On the other hand, we observed that constitutive and inducible levels of the IL-18-processing enzyme caspase-1 were markedly reduced in the spleen and the liver of IRF-1 KO compared to WT mice. In addition, both constitutive and inducible liver mRNA levels for the IL-18 binding protein (IL-18BP), a specific IL-18 antagonist, were significantly lower in IRF-1 KO than in WT mice. Compared to IL-12, IL-18 only weakly induced IRF-1 mRNA in cultured splenocytes. However, IL-18-induced IFN-gamma production was strongly reduced in splenocytes from IRF-1 KO compared to WT cells. In conclusion, IRF-1 regulates IL-18 production and activity mostly by modulating expression of caspase-1 and IL-18BP. In addition, IRF-1 participates in the induction of IFN-gamma by IL-18.
Fantuzzi
G
G
Department of Medicine, University of Colorado Health Sciences Center, Denver, USA. Giamila.Fantuzzi@UCHSC.edu
Reed
D
D
Qi
M
M
Scully
S
S
Dinarello
C A
CA
Senaldi
G
G
D000818:Animals; D020170:Caspase 1 / Q000235:genetics; D004268:DNA-Binding Proteins / Q000502:physiology*; D005260:Female; D050856:Interferon Regulatory Factor-1; D007371:Interferon-gamma / Q000096:biosynthesis; D020382:Interleukin-18 / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D053727:Interleukin-18 Receptor alpha Subunit; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D018123:Receptors, Interleukin / Q000235:genetics; D053724:Receptors, Interleukin-18
D004268:DNA-Binding Proteins; C508573:Il18r1 protein, mouse; D050856:Interferon Regulatory Factor-1; D020382:Interleukin-18; D053727:Interleukin-18 Receptor alpha Subunit; C494258:Irf1 protein, mouse; D010750:Phosphoproteins; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053724:Receptors, Interleukin-18; D007371:Interferon-gamma; D020170:Caspase 1