title: TGF-beta1 dampens the susceptibility of dendritic cells to environmental stimulation, leading to the requirement for danger signals for activation.
abstract: In contrast to its favourable effects on Langerhans cell (LC) differentiation, transforming growth factor (TGF)-beta1 has been reported to prevent dendritic cells from maturing in response to tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta, or lipopolysaccharide (LPS). We first characterized the effects of TGF-beta1 on dendritic cell function by testing the response of TGF-beta1-treated monocyte-derived dendritic cells (MoDCs) to maturation stimuli that LCs receive in the epidermis, namely, haptens, ATP and ultraviolet (UV). TGF-beta1 treatment, which augmented E-cadherin and down-regulated dendritic cell-specific ICAM3-grabbing non-integrin on MoDCs, significantly suppressed their CD86 expression and hapten-induced expression of IL-1beta and TNF-alpha mRNA and protein. As TGF-beta1-treated MoDCs lacked Langerin expression, we demonstrated the suppressive effects of TGF-beta1 on haematopoietic progenitor cell-derived dendritic cells expressing both CD1a and Langerin. These suppressive effects of TGF-beta1 increased with the duration of treatment. Furthermore, TGF-beta1-treated MoDCs became resistant to apoptosis/necrosis induced by high hapten, ATP or UV doses. This was mainly attributable to dampened activation of p38 mitogen-activated protein kinase (MAPK) in TGF-beta1-treated MoDCs. Notably, although ATP or hapten alone could only induce CD86 expression weakly and could not augment the allogeneic T-cell stimulatory function of TGF-beta1-treated MoDCs, ATP and hapten synergized to stimulate these phenotypic and functional changes. Similarly, 2,4-dinitro, 1-chlorobenzene (DNCB) augmented the maturation of TGF-beta1-treated MoDCs upon co-culture with a keratinocyte cell line, in which ATP released by the hapten-stimulated keratinocytes synergized with the hapten to induce their maturation. These data may suggest that TGF-beta1 protects LCs from being overactivated by harmless environmental stimulation, while maintaining their ability to become activated in response to danger signals released by keratinocytes.
authors.affiliation: Department of Dermatology, Tohoku University Graduate School of Medicine, Seiryo-machi, Aobaku, Sendai, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Ohtani
authors.forename: Masato
authors.initials: M
authors.lastname: Mizuashi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nakagawa
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Sasaki
authors.forename: Taku
authors.initials: T
authors.lastname: Fujimura
authors.forename: Ryuhei
authors.initials: R
authors.lastname: Okuyama
authors.forename: Setsuya
authors.initials: S
authors.lastname: Aiba
mesh_terms: D000255:Adenosine Triphosphate / Q000276:immunology; D018952:Antigens, CD34 / Q000032:analysis; D017209:Apoptosis / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D004137:Dinitrochlorobenzene / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D006241:Haptens / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance; D015603:Keratinocytes / Q000276:immunology; D007801:Langerhans Cells / Q000276:immunology; D009336:Necrosis / Q000276:immunology; D053773:Transforming Growth Factor beta1 / Q000276:immunology*; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D018952:Antigens, CD34; D004137:Dinitrochlorobenzene; D006241:Haptens; D053773:Transforming Growth Factor beta1; D000255:Adenosine Triphosphate; D048051:p38 Mitogen-Activated Protein Kinases