IFN-γ controls IL-33 protein level through a STAT1- and LMP2-dependent mechanism (CCR5P.268)

IL-33 levels and activity are differentially associated with Th1 and Th2 phenotypes. IL-33 mRNA is rapidly regulated but the fate of synthesized IL-33 protein is unknown. To assess the interplay between IL-33, IFN-γ, and IL-4 proteins, replication-deficient adenoviruses (AdV) were constructed for du...

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Published inThe Journal of immunology (1950) Vol. 192; no. 1_Supplement; pp. 181 - 181.22
Main Authors Kopach, Pavel, Lockatell, Virginia, Todd, Nevins, Luzina, Irina, Atamas, Sergei
Format Journal Article
LanguageEnglish
Published 01.05.2014
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Abstract IL-33 levels and activity are differentially associated with Th1 and Th2 phenotypes. IL-33 mRNA is rapidly regulated but the fate of synthesized IL-33 protein is unknown. To assess the interplay between IL-33, IFN-γ, and IL-4 proteins, replication-deficient adenoviruses (AdV) were constructed for dual expression of IL-33 & IFN-γ or of IL-33 & IL-4. Combined IL-33 & IFN-γ or IL-33 & IL-4 effects were compared with similar AdV expression of each of these cytokines alone. Co-delivery of IL-33 & IFN-γ led to mutual suppression, and co-delivery of IL-33 & IL-4 led to mutual elevation of these proteins in cell culture and in vivo. Purified IFN-γ also attenuated IL-33 protein but not mRNA driven by the recombinant CMV promoter in AdV-IL-33-infected cells, suggesting that IFN-γ controls IL-33 protein degradation. Pharmacological inhibition, siRNA-mediated silencing, or gene deficiency of STAT1 potently upregulated IL-33 protein expression levels and attenuated the downregulating effect of IFN-γ on IL-33. Inhibition of caspase-1, -3, or -8 had minimal effect on IFN-γ-driven IL-33 protein downregulation. siRNA-mediated silencing of LMP2 proteasome subunit, which is known to be essential for IFN-γ-regulated antigen processing, also abrogated the effect of IFN-γ on IL-33. Thus, IL-33, IFN-γ, and IL-4 are engaged in a complex interplay, part of which involves IFN-γ-activated, caspase-independent, STAT1-mediated degradation of IL-33 protein through non-canonical use of LMP2 proteasome.
AbstractList IL-33 levels and activity are differentially associated with Th1 and Th2 phenotypes. IL-33 mRNA is rapidly regulated but the fate of synthesized IL-33 protein is unknown. To assess the interplay between IL-33, IFN-γ, and IL-4 proteins, replication-deficient adenoviruses (AdV) were constructed for dual expression of IL-33 & IFN-γ or of IL-33 & IL-4. Combined IL-33 & IFN-γ or IL-33 & IL-4 effects were compared with similar AdV expression of each of these cytokines alone. Co-delivery of IL-33 & IFN-γ led to mutual suppression, and co-delivery of IL-33 & IL-4 led to mutual elevation of these proteins in cell culture and in vivo. Purified IFN-γ also attenuated IL-33 protein but not mRNA driven by the recombinant CMV promoter in AdV-IL-33-infected cells, suggesting that IFN-γ controls IL-33 protein degradation. Pharmacological inhibition, siRNA-mediated silencing, or gene deficiency of STAT1 potently upregulated IL-33 protein expression levels and attenuated the downregulating effect of IFN-γ on IL-33. Inhibition of caspase-1, -3, or -8 had minimal effect on IFN-γ-driven IL-33 protein downregulation. siRNA-mediated silencing of LMP2 proteasome subunit, which is known to be essential for IFN-γ-regulated antigen processing, also abrogated the effect of IFN-γ on IL-33. Thus, IL-33, IFN-γ, and IL-4 are engaged in a complex interplay, part of which involves IFN-γ-activated, caspase-independent, STAT1-mediated degradation of IL-33 protein through non-canonical use of LMP2 proteasome.
Author Luzina, Irina
Kopach, Pavel
Atamas, Sergei
Todd, Nevins
Lockatell, Virginia
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