Induction of an anti-inflammatory cytokine, IL-10, in dendritic cells after toll-like receptor signaling.
Interleukin-10 (IL-10) is an anti-inflammatory cytokine that modulates innate and adaptive immunity. IL-10 transcripts and the protein were induced in murine bone marrow-derived dendritic cells (BMDCs) after toll-like receptor (TLR) stimulation. IL-10 induction was TLR ligand selective, in that CpG DNA, imidazoquinolin, peptidoglycan, and zymosan but not lipopolysaccharide (LPS) and poly I:C led to IL-10 production. IL-10 induction was, however, completely absent in MyD88(/) DCs that lacked a TLR adaptor showing that IL-10 induction depends on TLR signaling. Kinetic analysis of IL-10 induction by CpG and imidazoquinolin revealed a prolonged lag phase prior to a measurable rise in transcript levels, which peaked at 12-24 h after stimulation. Stat3, implicated in IL-10 gene transcription, was also induced after TLR stimulation with the kinetics similar to those of IL-10 induction. Further, Stat3 was phosphorylated and bound to the IL-10 promoter in TLR-stimulated DCs. Supporting a link with IL-10 induction, STAT3 induction was absent in MyD88(/) DCs. These data suggest a two-step model where the initial TLR signaling induced proinflammatory cytokines, which then activated Stat3, leading to the induction of IL-10. TLR-stimulated IL-10 production may regulate DC maturation steps, thereby influencing the ensuing immune responses.
Samarasinghe
Ranmal
R
Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
Tailor
Prafullakumar
P
Tamura
Tomohiko
T
Kaisho
Tsuneyasu
T
Akira
Shizuo
S
Ozato
Keiko
K
D000818:Animals; D019898:Autocrine Communication; D003713:Dendritic Cells / Q000276:immunology*; D005786:Gene Expression Regulation; D007093:Imidazoles / Q000494:pharmacology; D007249:Inflammation / Q000276:immunology; D016753:Interleukin-10 / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D008024:Ligands; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000502:physiology; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D019899:Paracrine Communication; D010457:Peptidoglycan / Q000494:pharmacology; D011070:Poly I-C / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000819:agonists / Q000502:physiology*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D015054:Zymosan / Q000494:pharmacology
C408982:CPG-oligonucleotide; D007093:Imidazoles; D008024:Ligands; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D009838:Oligodeoxyribonucleotides; D010457:Peptidoglycan; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D051193:Toll-Like Receptors; D016753:Interleukin-10; D015054:Zymosan; D011070:Poly I-C