title: Bystander inhibition of dendritic cell differentiation by Mycobacterium tuberculosis-induced IL-10.
abstract: Mycobacterium tuberculosis (Mtb) evades the immune response by impairing the functions of different antigen-presenting cells. We have recently shown that Mtb hijacks differentiation of monocytes into dendritic cells (DCs). To further characterize the mechanisms underlying this process, we investigated the consequences of inducing dendritic cell differentiation using interferon-α and granulocyte-macrophage colony-stimulating factor in the presence of supernatants (SNs) obtained from monocyte cultures treated with or without heat-inactivated Mtb. Although the SNs from control cultures do not interfere with the generation of fully differentiated DCs, monocytes stimulated with SNs from Mtb-stimulated cells (SN Mtb) remained CD14(+) and poorly differentiated into CD1a(+) cells. Among cytokines known to affect dendritic cell differentiation, we observed a robust production of interleukin-1β, interleukin-6, interleukin-10 and tumor necrosis factor-α upon Mtb stimulation. However, only interleukin-10 neutralization through the addition of soluble interleukin-10 receptor reversed the inhibitory activity of SN Mtb. Accordingly, the addition of recombinant interleukin-10 was able to significantly reduce CD1a expression. The interaction of Mtb with differentiating monocytes rapidly activates p38 mitogen-activated protein kinase, signal transducer and activator of transcription pathways, which are likely involved in interleukin-10 gene expression. Taken together, our results suggest that Mtb may inhibit the differentiation of bystander non-infected monocytes into DCs through the release of interleukin-10. These results shed light on new aspects of the host-pathogen interaction, which might help to identify innovative immunological strategies to limit Mtb virulence.
authors.affiliation: Department of Infectious, Parasitic and Immune-mediated Diseases, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Maria Elena
authors.initials: ME
authors.lastname: Remoli
authors.forename: Elena
authors.initials: E
authors.lastname: Giacomini
authors.forename: Elisa
authors.initials: E
authors.lastname: Petruccioli
authors.forename: Valerie
authors.initials: V
authors.lastname: Gafa
authors.forename: Martina
authors.initials: M
authors.lastname: Severa
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Gagliardi
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Iona
authors.forename: Richard
authors.initials: R
authors.lastname: Pine
authors.forename: Roberto
authors.initials: R
authors.lastname: Nisini
authors.forename: Eliana Marina
authors.initials: EM
authors.lastname: Coccia
mesh_terms: D024201:Bystander Effect / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D017077:Culture Media, Conditioned / Q000737:chemistry / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology*; D006801:Humans; D016898:Interferon-alpha / Q000276:immunology / Q000378:metabolism; D016753:Interleukin-10 / Q000276:immunology*; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000276:immunology / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D014376:Tuberculosis / Q000276:immunology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D017077:Culture Media, Conditioned; D016207:Cytokines; D016898:Interferon-alpha; D050796:STAT3 Transcription Factor; D016753:Interleukin-10; D048051:p38 Mitogen-Activated Protein Kinases