Specific TLR ligands regulate APRIL secretion by dendritic cells in a PKR-dependent manner.
A proliferation inducing ligand (APRIL) and B cell activating factor belonging to the TNF family (BAFF/BLyS) have been implicated in IgA class switch recombination in thymus-independent (TI) B cell responses. Dendritic cells (DC) are thought to regulate Ig class switching in TI B cell responses by providing B cells with cytokines, including APRIL and BAFF. We therefore set out to analyze the regulation of APRIL and BAFF expression by human monocyte-derived DC (moDC). We observed that moDC produce and secrete APRIL, but could not detect expression of BAFF. Importantly, stimulation with the Toll-like receptor ligands CpG and poly I:C specifically induced APRIL production, while other Toll-like receptor ligands were ineffective. The increase in APRIL was dependent on translation, but surprisingly not transcription. Instead, enhanced APRIL production and secretion resulted from activation of protein kinase receptor (PKR), as it was completely inhibited by the specific inhibitor of PKR, 2-aminopurine. This suggests that the specific induction of APRIL by CpG and poly I:C, and the signal integration by PKR, are regulated by translational modification and hint at a role for APRIL in the TI B cell response to viral infections.
Hardenberg
Gijs
G
Laboratory of Experimental Oncology and Radiobiology, Academic Medical Center, Amsterdam, The Netherlands.
Planelles
Lourdes
L
Schwarte
Carla M
CM
van Bostelen
Liesbeth
L
Le Huong
Tran
T
Hahne
Michael
M
Medema
Jan Paul
JP
D002478:Cells, Cultured; D003713:Dendritic Cells / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D004789:Enzyme Activation / Q000276:immunology; D006801:Humans; D007700:Kinetics; D008024:Ligands; D009838:Oligodeoxyribonucleotides / Q000378:metabolism / Q000494:pharmacology; D011070:Poly I-C / Q000378:metabolism / Q000494:pharmacology; D051193:Toll-Like Receptors / Q000378:metabolism*; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000378:metabolism*; D019892:eIF-2 Kinase / Q000378:metabolism / Q000502:physiology*
C408982:CPG-oligonucleotide; D008024:Ligands; D009838:Oligodeoxyribonucleotides; C114631:TNFSF13 protein, human; D051193:Toll-Like Receptors; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; D019892:eIF-2 Kinase; D011070:Poly I-C