title: Spleen tyrosine kinase regulates AP-1 dependent transcriptional response to minimally oxidized LDL.
abstract: Oxidative modification of low-density lipoprotein (LDL) turns it into an endogenous ligand recognized by pattern-recognition receptors. We have demonstrated that minimally oxidized LDL (mmLDL) binds to CD14 and mediates TLR4/MD-2-dependent responses in macrophages, many of which are MyD88-independent. We have also demonstrated that the mmLDL activation leads to recruitment of spleen tyrosine kinase (Syk) to TLR4 and TLR4 and Syk phosphorylation. In this study, we produced a macrophage-specific Syk knockout mouse and used primary Syk(-/-) macrophages in our studies. We demonstrated that Syk mediated phosphorylation of ERK1/2 and JNK, which in turn phosphorylated c-Fos and c-Jun, respectively, as assessed by an in vitro kinase assay. c-Jun phosphorylation was also mediated by IKKε. c-Jun and c-Fos bound to consensus DNA sites and thereby completed an AP-1 transcriptional complex and induced expression of CXCL2 and IL-6. These results suggest that Syk plays a key role in TLR4-mediated macrophage responses to host-generated ligands, like mmLDL, with subsequent activation of an AP-1 transcription program.
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Soo-Ho
authors.initials: SH
authors.lastname: Choi
authors.forename: Philipp
authors.initials: P
authors.lastname: Wiesner
authors.forename: Felicidad
authors.initials: F
authors.lastname: Almazan
authors.forename: Jungsu
authors.initials: J
authors.lastname: Kim
authors.forename: Yury I
authors.initials: YI
authors.lastname: Miller
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D016466:CHO Cells; D054426:Chemokine CXCL2 / Q000378:metabolism; D006224:Cricetinae; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism / Q000502:physiology*; D018950:Lipopolysaccharide Receptors / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism / Q000502:physiology*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D000072377:Syk Kinase; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D018950:Lipopolysaccharide Receptors; D008077:Lipoproteins, LDL; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D018808:Transcription Factor AP-1; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D051550:I-kappa B Kinase