title: Modulation of MMP-2 (gelatinase A) and MMP-9 (gelatinase B) by interferon-gamma in a human salivary gland cell line.
abstract: Gelatinases have been shown to be regulated by many cytokines and growth factors, and have been implicated in the pathogenesis of certain autoimmune diseases via tissue destruction. High levels of several cytokines, including IFN-gamma and TNF-alpha, have been demonstrated in the salivary gland microenvironment of patients with Sjogren's syndrome (SS). How these cytokines may be contributing to the pathogenesis of this disease is not well understood. We hypothesized that IFN-gamma with or without (+/-) TNF-alpha could be playing a role in the pathogenesis of SS via the regulation of matrix metalloproteinase (MMP) levels. This study examined the role of IFN-gamma and (+) TNF-alpha in the regulation of the matrix metalloproteinases, MMP-2 (72 kD gelatinase A) and MMP-9 (92 kD gelatinase B). A human salivary gland cell line (HSG) has been used as a possible in vitro model to study the role of IFN-gamma + TNF-alpha in the pathogenesis of SS. The HSG cell line, in the presence of IFN +/- TNF-alpha, displays increased MMP-2 and MMP-9 gelatinolytic activity, protein and RNA levels. The increase in MMP activity was partially blocked with an antibody against the IFN-gamma receptor, and this was associated with a complete inhibition of the previously described IFN-gamma +/- TNF-alpha antiproliferative effect. However, incubation of IFN-gamma treated HSG cells with the synthetic MMP inhibitor BB94 did not alleviate this antiproliferative effect. In addition, we demonstrate that there are very high levels of MMP-9 in the saliva of patients with SS when compared to healthy control subjects. These data suggest that cytokines could be regulating MMP production by salivary epithelial cells and thus indicate a potential role for these cells in the pathogenesis of SS.
authors.affiliation: Clinical Investigations and Patient Care Branch, National Institute of Dental Research, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Wu
authors.forename: R M
authors.initials: RM
authors.lastname: Lafrenie
authors.forename: C
authors.initials: C
authors.lastname: Park
authors.forename: W
authors.initials: W
authors.lastname: Apinhasmit
authors.forename: Z J
authors.initials: ZJ
authors.lastname: Chen
authors.forename: H
authors.initials: H
authors.lastname: Birkedal-Hansen
authors.forename: K M
authors.initials: KM
authors.lastname: Yamada
authors.forename: W G
authors.initials: WG
authors.lastname: Stetler-Stevenson
authors.forename: B J
authors.initials: BJ
authors.lastname: Baum
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D001667:Binding, Competitive / Q000276:immunology; D015152:Blotting, Northern; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D017364:Collagenases / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells; D004848:Epithelium / Q000187:drug effects / Q000201:enzymology; D018093:Gelatinases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D010306:Parotid Gland / Q000166:cytology* / Q000201:enzymology; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D017471:Receptors, Interferon / Q000276:immunology; D012463:Saliva / Q000201:enzymology; D012859:Sjogren's Syndrome / Q000378:metabolism; D013876:Thiophenes / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000911:Antibodies, Monoclonal; D011480:Protease Inhibitors; D012333:RNA, Messenger; D017471:Receptors, Interferon; D013876:Thiophenes; D014409:Tumor Necrosis Factor-alpha; D010649:Phenylalanine; D007371:Interferon-gamma; C080985:batimastat; D017364:Collagenases; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9