title: IFN-γ directly controls IL-33 protein level through a STAT1- and LMP2-dependent mechanism.
abstract: IL-33 contributes to disease processes in association with Th1 and Th2 phenotypes. IL-33 mRNA is rapidly regulated, but the fate of synthesized IL-33 protein is unknown. To understand the interplay among IL-33, IFN-γ, and IL-4 proteins, recombinant replication-deficient adenoviruses were produced and used for dual expression of IL-33 and IFN-γ or IL-33 and IL-4. The effects of such dual gene delivery were compared with the effects of similar expression of each of these cytokines alone. In lung fibroblast culture, co-expression of IL-33 and IFN-γ resulted in suppression of the levels of both proteins, whereas co-expression of IL-33 and IL-4 led to mutual elevation. In vivo, co-expression of IL-33 and IFN-γ in the lungs led to attenuation of IL-33 protein levels. Purified IFN-γ also attenuated IL-33 protein in fibroblast culture, suggesting that IFN-γ controls IL-33 protein degradation. Specific inhibition of caspase-1, -3, and -8 had minimal effect on IFN-γ-driven IL-33 protein down-regulation. Pharmacological inhibition, siRNA-mediated silencing, or gene deficiency of STAT1 potently up-regulated IL-33 protein expression levels and attenuated the down-regulating effect of IFN-γ on IL-33. Stimulation with IFN-γ strongly elevated the levels of the LMP2 proteasome subunit, known for its role in IFN-γ-regulated antigen processing. siRNA-mediated silencing of LMP2 expression abrogated the effect of IFN-γ on IL-33. Thus, IFN-γ, IL-4, and IL-33 are engaged in a complex interplay. The down-regulation of IL-33 protein levels by IFN-γ in pulmonary fibroblasts and in the lungs in vivo occurs through STAT1 and non-canonical use of the LMP2 proteasome subunit in a caspase-independent fashion.
authors.affiliation: University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors.forename: Pavel
authors.initials: P
authors.lastname: Kopach
authors.affiliation: University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors.forename: Virginia
authors.initials: V
authors.lastname: Lockatell
authors.affiliation: University of Maryland School of Medicine, Baltimore, Maryland 21201; Baltimore Veterans Affairs Medical Center, Baltimore, Maryland 21201.
authors.forename: Edward M
authors.initials: EM
authors.lastname: Pickering
authors.affiliation: ViraQuest Inc., North Liberty, Iowa 52317.
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Haskell
authors.affiliation: ViraQuest Inc., North Liberty, Iowa 52317.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Anderson
authors.affiliation: University of Maryland School of Medicine, Baltimore, Maryland 21201; Baltimore Veterans Affairs Medical Center, Baltimore, Maryland 21201.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Hasday
authors.affiliation: University of Maryland School of Medicine, Baltimore, Maryland 21201; Baltimore Veterans Affairs Medical Center, Baltimore, Maryland 21201.
authors.forename: Nevins W
authors.initials: NW
authors.lastname: Todd
authors.affiliation: University of Maryland School of Medicine, Baltimore, Maryland 21201; Baltimore Veterans Affairs Medical Center, Baltimore, Maryland 21201.
authors.forename: Irina G
authors.initials: IG
authors.lastname: Luzina
authors.affiliation: University of Maryland School of Medicine, Baltimore, Maryland 21201; Baltimore Veterans Affairs Medical Center, Baltimore, Maryland 21201. Electronic address: satamas@umaryland.edu.
authors.forename: Sergei P
authors.initials: SP
authors.lastname: Atamas
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000502:physiology*; D015536:Down-Regulation; D005260:Female; D007371:Interferon-gamma / Q000502:physiology*; D015847:Interleukin-4 / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D041681:NIH 3T3 Cells; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000502:physiology*
chemical_list: D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; C071313:LMP-2 protein; D015847:Interleukin-4; D007371:Interferon-gamma; D003546:Cysteine Endopeptidases
keywords: Caspase; Cytokines/Interferon; Immunology; Inflammation; Interferon-γ; Interleukin; Interleukin-33; Interleukin-4; LMP2; STAT1