title: Endothelin Receptors Expressed by Immune Cells Are Involved in Modulation of Inflammation and in Fibrosis: Relevance to the Pathogenesis of Systemic Sclerosis.
abstract: Endothelin-1 (ET-1) plays a pivotal role in vasoconstriction, fibrosis, and inflammation, the key features of systemic sclerosis (SSc). ET-1 receptors (ETA and ET(B)) are expressed on endothelial cells, smooth muscle cells, and fibroblasts, but their presence on immune cells has not been deeply investigated so far. Endothelin receptors antagonists such as bosentan have beneficial effects on vasoconstriction and fibrosis, but less is known about their potential anti-inflammatory effects. We studied the expression of ET-1 receptors on immune cells (T and B lymphocytes, monocytes, and neutrophils) and the link between ET-1 and inflammation in patients with SSc. We show here that ET-1 exerts a proinflammatory effect in CD4+ T cells, since it induces an increased IFN-γ production; preincubation with antagonists of both receptors reduces IFN-γ production. Moreover, following ET-1 stimulation, neutrophils produce proinflammatory mediators, thus amplifying the effects of activated CD4+ T cells. Our data indicate that ET-1 system is involved in the pathogenesis of inflammation and fibrosis typical of SSc, through the activation of T lymphocytes and neutrophils and the consequent release of proinflammatory and profibrotic cytokines. These findings suggest that dual ET-1 receptors antagonist therapy, besides its effect on vasculopathy, has a profound impact on the immune system favouring antiinflammatory and antifibrogenic effects.
authors.affiliation: Department of Medicine, University of Verona, 37134 Verona, Italy.
authors.forename: Tinazzi
authors.initials: T
authors.lastname: Elisa
authors.affiliation: G. Gaslini Institute, 16148 Genoa, Italy ; University of Genoa, 16126 Genoa, Italy.
authors.forename: Puccetti
authors.initials: P
authors.lastname: Antonio
authors.affiliation: Department of Medicine, University of Verona, 37134 Verona, Italy.
authors.forename: Patuzzo
authors.initials: P
authors.lastname: Giuseppe
authors.affiliation: Department of Medicine, University of Verona, 37134 Verona, Italy.
authors.forename: Barbieri
authors.initials: B
authors.lastname: Alessandro
authors.affiliation: Department of Medicine, University of Verona, 37134 Verona, Italy.
authors.forename: Argentino
authors.initials: A
authors.lastname: Giuseppe
authors.affiliation: Department of Medicine, University of Verona, 37134 Verona, Italy.
authors.forename: Confente
authors.initials: C
authors.lastname: Federico
authors.affiliation: G. Gaslini Institute, 16148 Genoa, Italy.
authors.forename: Dolcino
authors.initials: D
authors.lastname: Marzia
authors.affiliation: Department of Medicine, University of Verona, 37134 Verona, Italy.
authors.forename: Beri
authors.initials: B
authors.lastname: Ruggero
authors.affiliation: Department of Medicine, University of Verona, 37134 Verona, Italy.
authors.forename: Marchi
authors.initials: M
authors.lastname: Giacomo
authors.affiliation: University of Genoa, 16126 Genoa, Italy.
authors.forename: Ottria
authors.initials: O
authors.lastname: Andrea
authors.affiliation: Pederzoli Hospital, Peschiera del Garda, 37019 Verona, Italy.
authors.forename: Righetti
authors.initials: R
authors.lastname: Daniela
authors.affiliation: Pederzoli Hospital, Peschiera del Garda, 37019 Verona, Italy.
authors.forename: Rampudda
authors.initials: R
authors.lastname: Mariaelisa
authors.affiliation: Department of Medicine, University of Verona, 37134 Verona, Italy.
authors.forename: Lunardi
authors.identifier: 0000-0001-6446-2990
authors.initials: L
authors.lastname: Claudio
mesh_terms: D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D000077300:Bosentan; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D065128:Endothelin Receptor Antagonists / Q000627:therapeutic use; D019332:Endothelin-1 / Q000276:immunology / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D005355:Fibrosis / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D007371:Interferon-gamma / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D017466:Receptors, Endothelin / Q000276:immunology* / Q000378:metabolism*; D012595:Scleroderma, Systemic / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D013449:Sulfonamides / Q000627:therapeutic use
chemical_list: D000893:Anti-Inflammatory Agents; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D017466:Receptors, Endothelin; D013449:Sulfonamides; D007371:Interferon-gamma; D000077300:Bosentan