title: Distinct responses of lung and spleen dendritic cells to the TLR9 agonist CpG oligodeoxynucleotide.
abstract: Dendritic cells (DCs) sense various components of invading pathogens via pattern recognition receptors such as TLRs. CpG oligodeoxynucleotides (ODNs), which mimic bacterial DNA, inhibit allergic airways disease and promote responses in the spleen to bacterial components. Because many TLR agonists are currently being tested for potential therapeutic effects, it is important to characterize the expression and function of TLRs in different tissues. We show that both myeloid and plasmacytoid DCs in the spleen express TLR9, the receptor for CpG ODNs, but lung DCs show no detectable expression in either subset. TLR4 expression in contrast was detected on both lung and spleen DCs. LPS was superior to CpG ODN in increasing the allostimulatory potential of lung DCs and their expression of CD40. However, both agonists efficiently stimulated spleen DCs. CpG ODNs administered to mice efficiently inhibited Th2 cytokine production both in the lung draining lymph node and in the spleen. Surprisingly, inhibition of Th2 cytokine production was evident despite high levels of expression of GATA-3 and additional transcription factors that regulate Th2 responses. Although in the spleen CpG ODNs induced IL-6, a key cytokine induced via TLR9-MyD88 signaling, no IL-6 was detectable in lung LN cells. These studies show for the first time that lung DCs lack TLR9 expression, but, despite this deficiency, CpG ODNs induce potent inhibitory effects on Th2 cytokine production in the lung without inducing expression of the proinflammatory cytokine, IL-6, which has been linked to chronic diseases in the lung and the gut.
authors.affiliation: Department of Medicine, Pulmonary, Allergy, and Critical Care Division, University of Pittsburgh School of Medicine, 3459 Fifth Avenue, Pittsburgh, PA 15213, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Arora
authors.forename: Manohar
authors.initials: M
authors.lastname: Yarlagadda
authors.forename: Timothy B
authors.initials: TB
authors.lastname: Oriss
authors.forename: Nandini
authors.initials: N
authors.lastname: Krishnamoorthy
authors.forename: Anuradha
authors.initials: A
authors.lastname: Ray
authors.forename: Prabir
authors.initials: P
authors.lastname: Ray
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D002469:Cell Separation; D002478:Cells, Cultured; D018899:CpG Islands / Q000276:immunology*; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D051217:Toll-Like Receptor 9 / Q000819:agonists*
chemical_list: D000276:Adjuvants, Immunologic; C408982:CPG-oligonucleotide; D009838:Oligodeoxyribonucleotides; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9