TGF-beta1 dampens the susceptibility of dendritic cells to environmental stimulation, leading to the requirement for danger signals for activation.
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.
Ohtani
Tomoyuki
T
Department of Dermatology, Tohoku University Graduate School of Medicine, Seiryo-machi, Aobaku, Sendai, Japan.
Mizuashi
Masato
M
Nakagawa
Satoshi
S
Sasaki
Yoshinori
Y
Fujimura
Taku
T
Okuyama
Ryuhei
R
Aiba
Setsuya
S
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
D018952:Antigens, CD34; D004137:Dinitrochlorobenzene; D006241:Haptens; D053773:Transforming Growth Factor beta1; D000255:Adenosine Triphosphate; D048051:p38 Mitogen-Activated Protein Kinases