title: Overexpression of SOCS3 in T lymphocytes leads to impaired interleukin-17 production and severe aortic aneurysm formation in mice--brief report.
abstract: OBJECTIVE
  Mutations of signal transducer and activator of transcription 3 (STAT3) are responsible for autosomal dominant hyperimmunoglobulin E syndrome. Recently, we reported frequent vascular abnormalities, including aneurysms in these patients, and demonstrated that STAT3 inhibition promoted aneurysm in mice. The purpose of this study was to investigate the role of cell-specific STAT3 signaling in the susceptibility to aneurysm.
  
  
  RESULTS
  C57BL/6 wild-type mice were irradiated and repopulated with bone marrow cells isolated from either wild-type mice or from mice with defective STAT3 signaling as a result of overexpression of suppressor of cytokine signaling 3 (SOCS3-Tg mice). Mice were then subjected to a validated model of abdominal aortic aneurysm induced by angiotensin II infusion for 28 days, along with repetitive injections of a neutralizing antitransforming growth factor-β antibody. We found that overexpression of SOCS3 in bone marrow-derived cells significantly increased aneurysm severity (P=0.04). In contrast, overexpression of SOCS3 in the vessel wall had no effect on the disease process. Surprisingly, deletion of STAT3 signaling in macrophages did not affect aneurysm development. Interestingly, however, defective STAT3 signaling in SOCS3-Tg T cells markedly increased aneurysm severity (P=0.01) and mortality from aneurysm rupture (P=0.008). Overexpression of SOCS3 in T cells significantly decreased interleukin-17 production (P<0.0001) and was associated with a reduction of its plasma levels (P=0.02).
  
  
  CONCLUSIONS
  These findings clearly identify a central role for T cell-specific STAT3 signaling in the promotion of vascular aneurysm and support previous work on interleukin-17 protective role in this process.
authors: Institut National de la Santé et de la Recherche Médicale (Inserm), Unit 970, Paris Cardiovascular Research Center, and Université Paris-Descartes, Paris, France.
authors: Mélissa
authors: M
authors: Romain
authors: Soraya
authors: S
authors: Taleb
authors: Marion
authors: M
authors: Dalloz
authors: Padmapriya
authors: P
authors: Ponnuswamy
authors: Bruno
authors: B
authors: Esposito
authors: Nicolas
authors: N
authors: Pérez
authors: Yu
authors: Y
authors: Wang
authors: Akihiko
authors: A
authors: Yoshimura
authors: Alain
authors: A
authors: Tedgui
authors: Ziad
authors: Z
authors: Mallat
mesh_terms: D000804:Angiotensin II; D000818:Animals; D057134:Antibodies, Neutralizing; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D001019:Aortic Rupture / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016026:Bone Marrow Transplantation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005838:Genotype; D020381:Interleukin-17 / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D010641:Phenotype; D050796:STAT3 Transcription Factor / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism*; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism*; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000276:immunology; D015854:Up-Regulation; D014916:Whole-Body Irradiation
chemical_list: D057134:Antibodies, Neutralizing; D020381:Interleukin-17; D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; C494087:Stat3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D016212:Transforming Growth Factor beta; D000804:Angiotensin II