title: Fibroblasts stimulated via HLA-II molecules produce prostaglandin E₂ and regulate cytokine production from helper T cells.
abstract: Fibroblasts act as important immune regulatory cells via their ability to cross-talk with T cells accumulating in lesions. Our previous study showed that fibroblasts produce several cytokines and chemokines by crosslinking HLA class II (HLA-II) molecules with monoclonal antibodies or by making T-cell receptor-peptide-HLA complexes. It is thus conceivable that the interaction of T cells and fibroblasts via HLA-II affects fibroblast responses to stimuli. This study used human gingival fibroblasts (HGF) to investigate possible effects of these fibroblast-derived soluble factors on the differentiation of naïve T cells and on the subsequent fibroblast responses. After mixed lymphocyte reaction culture between naïve T cells and allogeneic dendritic cells in the presence of culture supernatant from HGF stimulated via HLA-DQ molecules (DQ-sup), but not via DR, T cells exhibited a Th2-shifted phenotype, thereby producing quantitatively more IL-13 and IL-5 compared with interferon-γ. Astonishingly, analyses to identify possible factors affecting the Th2 polarization secreted from HLA-II-stimulated HGF, prostaglandin E₂, was detected only in DQ-sup. The Th2 polarization of naïve T cells was blocked in the presence of supernatants from indomethacin-treated HGF with HLA-DQ stimulation. In addition, we found that the culture supernatants of Th cells activated following mixed lymphocyte reaction culture in the presence of DQ-sup had the potential to induce gene expression of type I and III collagens in HGF. These results suggested that fibroblasts stimulated via HLA-DQ molecules promote Th2 polarization in Th-cell responses and showed the counter activation of collagen synthesis, implicating orchestrated responses among these cells in the fibrosis of chronic inflammatory lesions.
authors.affiliation: Department of Pathology, Hyogo College of Medicine, Nishinomiya, Japan.
authors.forename: Nahoko
authors.initials: N
authors.lastname: Kato-Kogoe
authors.forename: Hideki
authors.initials: H
authors.lastname: Ohyama
authors.forename: Fusanori
authors.initials: F
authors.lastname: Nishimura
authors.forename: Michio
authors.initials: M
authors.lastname: Meguro
authors.forename: Sayuri
authors.initials: S
authors.lastname: Yoshizawa
authors.forename: Yuka
authors.initials: Y
authors.lastname: Okada
authors.forename: Keiji
authors.initials: K
authors.lastname: Nakasho
authors.forename: Koji
authors.initials: K
authors.lastname: Yamanegi
authors.forename: Naoko
authors.initials: N
authors.lastname: Yamada
authors.forename: Masaki
authors.initials: M
authors.lastname: Hata
authors.forename: Takehiro
authors.initials: T
authors.lastname: Higashi
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Terada
authors.forename: Sho
authors.initials: S
authors.lastname: Matsushita
mesh_terms: D000328:Adult; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis* / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology; D005347:Fibroblasts / Q000187:drug effects / Q000276:immunology*; D005881:Gingiva / Q000276:immunology; D006683:HLA-DQ Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology*; D006801:Humans; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D018793:Interleukin-13 / Q000276:immunology / Q000378:metabolism; D015848:Interleukin-5 / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D011458:Prostaglandins E / Q000276:immunology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
chemical_list: D016207:Cytokines; D006683:HLA-DQ Antigens; D000949:Histocompatibility Antigens Class II; D018793:Interleukin-13; D015848:Interleukin-5; D011458:Prostaglandins E; D007371:Interferon-gamma