The RNA binding protein tristetraprolin influences the activation state of murine dendritic cells.
Dendritic cells (DCs) serve to maintain peripheral tolerance under steady state conditions. Upon triggering by activation signals they initiate strong immune responses. The activation of DCs is accompanied by a rapid upregulation of proinflammatory cytokines, which were shown in other cell types to be regulated by mechanisms at the transcriptional and posttranscriptional level. Tristetraprolin (TTP), an important RNA binding protein, is involved in the regulation of mRNA stability of such cytokines. In this study we analyzed the significance of TTP for mouse DCs, which were derived from TTP(-/-) and WT bone marrow progenitor cells (BM-DCs). Unstimulated BM-DCs of TTP(-/-) mice expressed lower levels of mRNAs encoding the costimulatory molecules CD40 and CD86 and surprisingly also the canonical TTP targets TNF-alpha and IL-10 as compared with WT DCs. On the protein level, both DC populations expressed comparable amounts of CD80 and CD86 and of either cytokine, but TTP(-/-) DCs expressed less MHCII than WT DCs. On the other hand, TTP(-/-) DCs displayed elevated expression of other TTP target mRNAs like IL-1beta, c-fos and Mkp-1. Stimulation of BM-DCs of either genotype with lipopolysaccharide resulted in a rapid upregulation to a comparable extent of all molecules monitored so far, except for c-fos mRNA. Subsequent mRNA decay analysis revealed gene-specific differences in mRNA stability, which was influenced by the presence of TTP and the activation state of the DCs. Unstimulated TTP(-/-) DCs exerted a markedly lower allogeneic T cell stimulatory potential than WT DCs. Moreover, TTP(-/-) DCs induced an altered cytokine pattern in cocultures of DCs and T cells. However, allogeneic T cells primed by unstimulated DCs of either genotype were equally refractory to restimulation and suppressed the proliferation of naive T cells to the same extent. Thus, the findings of this study lend support to the interpretation that without external stimulation antigen presenting activity in DCs in the presence of TTP is more pronounced than in its absence and that posttranscriptional regulation contributes to the control of gene expression in DCs.
Bros
Matthias
M
Department of Dermatology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany. mbros@uni-mainz.de
Wiechmann
Nadine
N
Besche
Verena
V
Art
Julia
J
Pautz
Andrea
A
Grabbe
Stephan
S
Kleinert
Hartmut
H
Reske-Kunz
Angelika B
AB
D000818:Animals; D051940:B7-2 Antigen / Q000096:biosynthesis / Q000276:immunology; D019013:CD40 Antigens / Q000096:biosynthesis / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D054638:Dual Specificity Phosphatase 1 / Q000096:biosynthesis / Q000276:immunology; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis / Q000276:immunology; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis / Q000276:immunology; D020871:RNA Stability / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000276:immunology*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051816:Tristetraprolin / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
D051940:B7-2 Antigen; D019013:CD40 Antigens; C497965:Cd86 protein, mouse; D000949:Histocompatibility Antigens Class II; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D051816:Tristetraprolin; C497553:Zfp36 protein, mouse; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse