title: Th2-predominant inflammation and blockade of IFN-gamma signaling induce aneurysms in allografted aortas.
abstract: Abdominal aortic aneurysms (AAAs) cause death due to complications related to expansion and rupture. The underlying mechanisms that drive AAA development remain largely unknown. We recently described evidence for a shift toward T helper type 2 (Th2) cell responses in human AAAs compared with stenotic atheromas. To evaluate putative pathways in AAA formation, we induced Th1- or Th2-predominant cytokine environments in an inflammatory aortic lesion using murine aortic transplantation into WT hosts or those lacking the receptors for the hallmark Th1 cytokine IFN-gamma, respectively. Allografts in WT recipients developed intimal hyperplasia, whereas allografts in IFN-gamma receptor-deficient (GRKO) hosts developed severe AAA formation associated with markedly increased levels of MMP-9 and MMP-12. Allografts in GRKO recipients treated with anti-IL-4 antibody to block the characteristic IL-4 Th2 cytokine or allografts in GRKO hosts also congenitally deficient in IL-4 did not develop AAA and likewise exhibited attenuated collagenolytic and elastolytic activities. These observations demonstrate an important dichotomy between cellular immune responses that induce IFN-gamma- or IL-4-dominated cytokine environments. The findings establish important regulatory roles for a Th1/Th2 cytokine balance in modulating matrix remodeling and have important implications for the pathophysiology of AAAs and arteriosclerosis.
authors.affiliation: The Donald W. Reynolds Cardiovascular Clinical Research Center, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. ksmz@rics.bwh.harvard.edu
authors.forename: Koichi
authors.initials: K
authors.lastname: Shimizu
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Shichiri
authors.forename: Peter
authors.initials: P
authors.lastname: Libby
authors.forename: Richard T
authors.initials: RT
authors.lastname: Lee
authors.forename: Richard N
authors.initials: RN
authors.lastname: Mitchell
mesh_terms: D000818:Animals; D001012:Aorta, Abdominal / Q000166:cytology / Q000378:metabolism / Q000473:pathology / Q000637:transplantation; D017544:Aortic Aneurysm, Abdominal / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D039481:CD11b Antigen / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D017471:Receptors, Interferon / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D018418:Th2 Cells / Q000276:immunology*; D014184:Transplantation, Homologous; D000096743:Interferon gamma Receptor
chemical_list: D039481:CD11b Antigen; D007371:Interferon-gamma; D015847:Interleukin-4; D020782:Matrix Metalloproteinases; D012333:RNA, Messenger; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor