title: A link between interferon and augmented plasmin generation in exocrine gland damage in Sjögren's syndrome.
abstract: Sjögren's syndrome is an autoimmune disease that targets exocrine glands, but often exhibits systemic manifestations. Infiltration of the salivary and lacrimal glands by lymphoid and myeloid cells orchestrates a perpetuating immune response leading to exocrine gland damage and dysfunction. Th1 and Th17 lymphocyte populations and their products recruit additional lymphocytes, including B cells, but also large numbers of macrophages, which accumulate with disease progression. In addition to cytokines, chemokines, chitinases, and lipid mediators, macrophages contribute to a proteolytic milieu, underlying tissue destruction, inappropriate repair, and compromised glandular functions. Among the proteases enhanced in this local environment are matrix metalloproteases (MMP) and plasmin, generated by plasminogen activation, dependent upon plasminogen activators, such as tissue plasminogen activator (tPA). Not previously associated with salivary gland pathology, our evidence implicates enhanced tPA in the context of inflamed salivary glands revolving around lymphocyte-mediated activation of macrophages. Tracking down the mechanism of macrophage plasmin activation, the cytokines IFNγ and to a lesser extent, IFNα, via Janus kinase (JAK) and signal transducer and activator of transcription (STAT) activation, were found to be pivotal for driving the plasmin cascade of proteolytic events culminating in perpetuation of the inflammation and tissue damage, and suggesting intervention strategies to blunt irreversible tissue destruction.
authors.affiliation: Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, MSC 4352, Bethesda, MD 20892-4352, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Gliozzi
authors.forename: Teresa
authors.initials: T
authors.lastname: Greenwell-Wild
authors.forename: Wenwen
authors.initials: W
authors.lastname: Jin
authors.forename: Niki M
authors.initials: NM
authors.lastname: Moutsopoulos
authors.forename: Efstathia
authors.initials: E
authors.lastname: Kapsogeorgou
authors.forename: Haralampos M
authors.initials: HM
authors.lastname: Moutsopoulos
authors.forename: Sharon M
authors.initials: SM
authors.lastname: Wahl
mesh_terms: D005088:Exocrine Glands / Q000276:immunology* / Q000473:pathology*; D005341:Fibrinolysin / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000276:immunology; D016898:Interferon-alpha; D007371:Interferon-gamma; D053612:Janus Kinases / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D020778:Matrix Metalloproteinase 2 / Q000276:immunology; D020780:Matrix Metalloproteinase 9 / Q000276:immunology; D010958:Plasminogen / Q000276:immunology; D010960:Plasminogen Activators / Q000378:metabolism; D050791:STAT Transcription Factors / Q000276:immunology / Q000378:metabolism; D012469:Salivary Glands / Q000276:immunology / Q000473:pathology; D012859:Sjogren's Syndrome / Q000276:immunology* / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology
chemical_list: D016898:Interferon-alpha; D050791:STAT Transcription Factors; D007371:Interferon-gamma; D010958:Plasminogen; D053612:Janus Kinases; D010960:Plasminogen Activators; D005341:Fibrinolysin; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9