title: Extracellular matrix-associated cytokines regulate CD4+ effector T-cell responses in the human intestinal mucosa.
abstract: Extracellular matrix (stroma) regulation of mucosal T-cell function is incompletely understood. In this study, we uncovered a role for intestinal stromal products in the innate regulation of effector T cells. Stroma-conditioned media (S-CM) derived from the normal human intestinal stroma (transforming growth factor-β (TGF-β)(hi)/interleukin (IL)-6(lo)/IL-1β(lo)) significantly downregulated T-cell proliferation and interferon-γ (IFN-γ) production compared with S-CM derived from the inflamed Crohn's mucosa (TGF-β(hi)/IL-6(hi)/IL-1β(hi)). Antibody neutralization studies showed that TGF-β in normal S-CM inhibited T-cell proliferation and IFN-γ production, whereas IL-6 plus IL-1β in Crohn's S-CM promoted T-cell proliferation, and IL-1β alone promoted IFN-γ and IL-17 release. Importantly, normal S-CM inhibited T-bet expression, whereas Crohn's S-CM activated signal transducer and activator of transcription 3, suggesting that discordant T-cell responses are regulated at the transcription factor and signaling levels. These findings implicate stromal TGF-β in the downregulation of T-cell 2 responses in the normal intestinal mucosa, and stromal IL-6 and IL-1β in the promotion of Th1 and Th17 responses in the inflamed Crohn's mucosa, suggesting an innate regulatory function for the intestinal extracellular matrix.
authors.affiliation: Department of Medicine (Gastroenterology), University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: K R
authors.initials: KR
authors.lastname: Huff
authors.forename: L N
authors.initials: LN
authors.lastname: Akhtar
authors.forename: A L
authors.initials: AL
authors.lastname: Fox
authors.forename: J A
authors.initials: JA
authors.lastname: Cannon
authors.forename: P D
authors.initials: PD
authors.lastname: Smith
authors.forename: L E
authors.initials: LE
authors.lastname: Smythies
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003424:Crohn Disease / Q000276:immunology / Q000473:pathology; D016207:Cytokines / Q000276:immunology*; D015536:Down-Regulation / Q000276:immunology; D005109:Extracellular Matrix / Q000276:immunology*; D006801:Humans; D018836:Inflammation Mediators / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology; D007413:Intestinal Mucosa / Q000276:immunology* / Q000473:pathology; D017154:Stromal Cells / Q000276:immunology / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D020381:Interleukin-17; D016212:Transforming Growth Factor beta