title: Constitutive phosphorylation of interferon receptor A-associated signaling proteins in systemic lupus erythematosus.
abstract: BACKGROUND
  Overexpression of type I interferon (IFN-I)-induced genes is a common feature of systemic lupus erythematosus (SLE) and its experimental models, but the participation of endogenous overproduction of IFN-I on it is not clear. To explore the possibility that abnormally increased IFN-I receptor (IFNAR) signaling could participate in IFN-I-induced gene overexpression of SLE, we examined the phosphorylation status of the IFNAR-associated signaling partners Jak1 and STAT2, and its relation with expression of its physiologic inhibitor SOCS1 and with plasma levels of IFNα and IFN-like activity.
  
  
  RESULTS
  Peripheral blood mononuclear cells (PBMC) from SLE patients with or without disease activity and healthy controls cultured in the presence or in the absence of IFNβ were examined by immunoprecipitation and/or western blotting for expression of the two IFNAR chains, Jak1, Tyk2, and STAT2 and their phosphorylated forms. In SLE but not in healthy control PBMC, Jak1 and STAT2 were constitutively phosphorylated, even in the absence of disease activity (basal pJak1: controls vs. active SLE p<0.0001 and controls vs. inactive SLE p = 0.0006; basal pSTAT2: controls vs. active and inactive SLE p<0.0001). Although SOCS1 protein was slightly but significantly decreased in SLE in the absence or in the presence of IFNβ (p = 0.0096 to p<0.0001), in SOCS1 mRNA levels were markedly decreased (p = 0.036 to p<0.0001). IFNβ induced higher levels of the IFN-I-dependent MxA protein mRNA in SLE than in healthy controls, whereas the opposite was observed for SOCS1. Although there was no relation to increased serum IFNα, active SLE plasma could induce expression of IFN-dependent genes by normal PBMC.
  
  
  CONCLUSIONS
  These findings suggest that in some SLE patients IFN-I dependent gene expression could be the result of a low IFNAR signaling threshold.
authors.affiliation: Research Unit on Autoimmune Diseases, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico, DF, Mexico.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Ramírez-Vélez
authors.forename: Francisco
authors.initials: F
authors.lastname: Medina
authors.forename: Luis
authors.initials: L
authors.lastname: Ramírez-Montaño
authors.forename: Abraham
authors.initials: A
authors.lastname: Zarazúa-Lozada
authors.forename: Ramiro
authors.initials: R
authors.lastname: Hernández
authors.forename: Luis
authors.initials: L
authors.lastname: Llorente
authors.forename: José
authors.initials: J
authors.lastname: Moreno
mesh_terms: D015088:2',5'-Oligoadenylate Synthetase / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D002478:Cells, Cultured; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016898:Interferon-alpha / Q000097:blood; D053613:Janus Kinase 1 / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000378:metabolism*; D008875:Middle Aged; D064547:Myxovirus Resistance Proteins; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D053633:Receptor, Interferon alpha-beta / Q000378:metabolism; D050795:STAT2 Transcription Factor / Q000378:metabolism*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D055815:Young Adult
chemical_list: D015852:Eukaryotic Initiation Factor-2; C507964:IFNAR1 protein, human; C508033:IFNAR2 protein, human; D016898:Interferon-alpha; C579071:MX1 protein, human; D064547:Myxovirus Resistance Proteins; C108944:SOCS1 protein, human; D050795:STAT2 Transcription Factor; C494084:STAT2 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D053633:Receptor, Interferon alpha-beta; C507904:JAK1 protein, human; D053613:Janus Kinase 1; D015088:2',5'-Oligoadenylate Synthetase; D019204:GTP-Binding Proteins