title: Inhibition of Protein Tyrosine Phosphatase 1B Improves IGF-I Receptor Signaling and Protects Against Inflammation-Induced Gliosis in the Retina.
abstract: OBJECTIVE
  Insulin-like growth factor-I receptor (IGF-IR) signaling mediates retinal growth and survival and its failure may contribute to aggravate diabetic retinopathy (DR). Protein tyrosine phosphatase 1B (PTP1B) negatively modulates IGF-IR signaling, but its involvement in inflammation during DR remains unknown. We investigated whether PTP1B participates in the cross-talk between proinflammatory signaling pathways and IGF-IR-mediated signaling in the retina.
  
  
  METHODS
  661W photoreceptors or mouse retinal explants were treated with TNFα, IL6, and IL1β. Insulin-like growth factor-I receptor signaling cascade was evaluated in the absence or presence of PTP1B. db/db mice were used to test a PTP1B inhibitor in retinal gliosis.
  
  
  RESULTS
  661W retinal cells and retinal explants responded to IGF-I by inducing IGF-IR tyrosine (13-fold) and Akt phosphorylations (7- and 3-fold for serine 473 and threonine 308, respectively). Cytokines triggered early activation of stress kinases (c-jun [NH2] terminal kinase [JNK] and p38 MAPK), resulting in insulin receptor substrate 1 (IRS1) serine 307 phosphorylation that precedes its degradation. Pretreatment of 661W cells or retinal explants with cytokines upregulated PTP1B protein levels (1.45- and 4.5-fold, respectively), induced IRS1 degradation and decreased IGF-I-mediated IGF-IR/Akt phosphorylation. Silencing or deficiency in PTP1B ameliorated the negative effects of cytokines on IGF-IR signaling. Cytokines increased glial fibrillary acidic protein (GFAP) expression in retinal explants by 4.5-fold, this response being reduced by 2-fold with a PTP1B inhibitor. Protein tyrosine phosphatase 1B protein levels increased by 3-fold in retinas from db/db mice and its inhibition reduced gliosis.
  
  
  CONCLUSIONS
  Targeting PTP1B might be useful for modulating IGF-I effects in retinal cells during DR.
authors.affiliation: Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Madrid, Spain 2Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC/UAM), Madrid, Spain.
authors.forename: Ana I
authors.initials: AI
authors.lastname: Arroba
authors.affiliation: Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Madrid, Spain 2Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC/UAM), Madrid, Spain.
authors.forename: Ángela M
authors.initials: ÁM
authors.lastname: Valverde
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002478:Cells, Cultured; D003930:Diabetic Retinopathy / Q000503:physiopathology*; D004195:Disease Models, Animal; D005911:Gliosis / Q000503:physiopathology*; D053583:Interleukin-1beta / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D020419:Photoreceptor Cells, Vertebrate / Q000187:drug effects / Q000502:physiology*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D017526:Receptor, IGF Type 1 / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D053583:Interleukin-1beta; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D017526:Receptor, IGF Type 1; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1