title: IFN-gamma-induced SOCS-1 regulates STAT6-dependent eotaxin production triggered by IL-4 and TNF-alpha.
abstract: The production of eotaxin, which is a critical mediator for airway inflammation, is inhibited by IFN-gamma. Here, we investigated the precise mechanisms underlying IFN-gamma-dependent inhibition of eotaxin production using mouse embryonic fibroblasts (MEF). MEF produced high levels of eotaxin in STAT6-dependent manner when they were cultured with both IL-4 and TNF-alpha. However, the eotaxin production by MEF was strongly inhibited by addition of IFN-gamma. Western-blotting analysis demonstrated that IFN-gamma downmodulated STAT6 phosphorylation induced by IL-4 and TNF-alpha. Moreover, IFN-gamma did not exhibit its inhibitory effect on both STAT6-phosphorylation and eotaxin production in MEF obtained from deficient mice in STAT1, a key molecule of IFN-gamma signaling. We also demonstrated that SOCS-1, a potent inhibitory molecule of IL-4 signaling, was induced by IFN-gamma in STAT1-dependent manner. This indicated that SOCS-1 might be involved in IFN-gamma-mediated STAT1-dependent inhibition of eotaxin production. In SOCS-1(-/-) MEF, IFN-gamma inhibited neither STAT6 phosphorylation nor eotaxin production induced by IL-4 and TNF-alpha. Conversely, retroviral transduction of SOCS-1 into MEF inhibited STAT6 phosphorylation and eotaxin production induced by IL-4 and TNF-alpha, in the absence of IFN-gamma. Thus, we demonstrated that IFN-gamma-induced inhibition of STAT6 phosphorylation and eotaxin production were mediated by SOCS-1 induced in STAT1-dependent manner.
authors.affiliation: Division of Immunoregulation, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sato
authors.forename: Rumina
authors.initials: R
authors.lastname: Saito
authors.forename: Takafumi
authors.initials: T
authors.lastname: Jinushi
authors.forename: Takemasa
authors.initials: T
authors.lastname: Tsuji
authors.forename: Junko
authors.initials: J
authors.lastname: Matsuzaki
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Koda
authors.forename: Shin ichiro
authors.initials: Si
authors.lastname: Nishimura
authors.forename: Hidetsugu
authors.initials: H
authors.lastname: Takeshima
authors.forename: Takashi
authors.initials: T
authors.lastname: Nishimura
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000378:metabolism*; D003001:Cloning, Molecular; D003470:Culture Media; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D007371:Interferon-gamma / Q000378:metabolism*; D015847:Interleukin-4 / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism / Q000502:physiology*; D012190:Retroviridae / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050800:STAT6 Transcription Factor; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; C515457:Ccl11 protein, mouse; D054413:Chemokine CCL11; D019742:Chemokines, CC; D003470:Culture Media; D018076:DNA, Complementary; D012333:RNA, Messenger; D012097:Repressor Proteins; D050800:STAT6 Transcription Factor; C491590:Socs1 protein, mouse; C494100:Stat6 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D014443:Tyrosine; D007371:Interferon-gamma