title: Syk negatively regulates TLR4-mediated IFNβ and IL-10 production and promotes inflammatory responses in dendritic cells.
abstract: BACKGROUND
  While Syk has been shown to associate with TLR4, the immune consequences of Syk-TLR interactions and related molecular mechanisms are unclear.
  
  
  METHODS
  Gain- and loss-of-function approaches were utilized to determine the regulatory function of Syk and elucidate the related molecular mechanisms in TLR4-mediated inflammatory responses. Cytokine production was measured by ELISA and phosphorylation of signaling molecules determined by Western blotting.
  
  
  RESULTS
  Syk deficiency in murine dendritic cells resulted in the enhancement of LPS-induced IFNβ and IL-10 but suppression of pro-inflammatory cytokines (TNFα, IL-6). Deficiency of Syk enhanced the activity of PI3K and elevated the phosphorylation of PI3K and Akt, which in turn, lead to the phospho-inactivation of the downstream, central gatekeeper of the innate response, GSK3β. Inhibition of PI3K or Akt abrogated the ability of Syk deficiency to enhance IFNβ and IL-10 in Syk deficient cells, confirmed by the overexpression of Akt (Myr-Akt) or constitutively active GSK3β (GSK3 S9A). Moreover, neither inhibition of PI3K-Akt signaling nor neutralization of de novo synthesized IFNβ could rescue TNFα and IL-6 production in LPS-stimulated Syk deficient cells. Syk deficiency resulted in decreased phosphorylation of IKKβ and the NF-κB p65 subunit, further suggesting a divergent influence of Syk on pro- and anti-inflammatory TLR responses.
  
  
  CONCLUSIONS
  Syk negatively regulates TLR4-mediated production of IFNβ and IL-10 and promotes inflammatory responses in dendritic cells through divergent regulation of downstream PI3K-Akt and NF-κB signaling pathways.
  
  
  CONCLUSIONS
  Syk may represent a novel target for manipulating the direction or intensity of the innate response, depending on clinical necessity.
authors.affiliation: Department of Infectious Diseases, Henan Provincial People's Hospital (Zhengzhou University People's Hospital), Zhengzhou, Henan 450001, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Yin
authors.affiliation: Department of Oral Immunology and Infectious Diseases, University of Louisville School of Dentistry, Louisville, KY 40202, USA.
authors.forename: Huaxin
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Infectious Diseases, Henan Provincial People's Hospital (Zhengzhou University People's Hospital), Zhengzhou, Henan 450001, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Kang
authors.affiliation: Department of Infectious Diseases, Henan Provincial People's Hospital (Zhengzhou University People's Hospital), Zhengzhou, Henan 450001, China.
authors.forename: Xiaoju
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Oral Immunology and Infectious Diseases, University of Louisville School of Dentistry, Louisville, KY 40202, USA.
authors.forename: Xiaoxian
authors.initials: X
authors.lastname: Duan
authors.affiliation: Department of Oral Immunology and Infectious Diseases, University of Louisville School of Dentistry, Louisville, KY 40202, USA.
authors.forename: Ridab
authors.initials: R
authors.lastname: Alnabhan
authors.affiliation: Department of Oral Immunology and Infectious Diseases, University of Louisville School of Dentistry, Louisville, KY 40202, USA.
authors.forename: Shuang
authors.initials: S
authors.lastname: Liang
authors.affiliation: Department of Oral Immunology and Infectious Diseases, University of Louisville School of Dentistry, Louisville, KY 40202, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Scott
authors.affiliation: Department of Oral Immunology and Infectious Diseases, University of Louisville School of Dentistry, Louisville, KY 40202, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Lamont
authors.affiliation: Department of Infectious Diseases, Henan Provincial People's Hospital (Zhengzhou University People's Hospital), Zhengzhou, Henan 450001, China. Electronic address: shangjia666@126.com.
authors.forename: Jia
authors.initials: J
authors.lastname: Shang
authors.affiliation: Department of Oral Immunology and Infectious Diseases, University of Louisville School of Dentistry, Louisville, KY 40202, USA. Electronic address: hhwang01@louisville.edu.
authors.forename: Huizhi
authors.initials: H
authors.lastname: Wang
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007249:Inflammation / Q000209:etiology*; D016899:Interferon-beta / Q000378:metabolism*; D007371:Interferon-gamma / Q000096:biosynthesis*; D016753:Interleukin-10 / Q000096:biosynthesis*; D015850:Interleukin-6 / Q000096:biosynthesis; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism; D000072377:Syk Kinase; D051197:Toll-Like Receptor 4 / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: C556062:IL10 protein, mouse; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D050791:STAT Transcription Factors; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D016899:Interferon-beta; D007371:Interferon-gamma; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3
keywords: GSK3β; IL-10; Interferon-β; PI3K; Syk; Toll-like receptor 4