IL-4 suppresses the responses to TLR7 and TLR9 stimulation and increases the permissiveness to retroviral infection of murine conventional dendritic cells.
Th2-inducing pathological conditions such as parasitic diseases increase susceptibility to viral infections through yet unclear mechanisms. We have previously reported that IL-4, a pivotal Th2 cytokine, suppresses the response of murine bone-marrow-derived conventional dendritic cells (cDCs) and splenic DCs to Type I interferons (IFNs). Here, we analyzed cDC responses to TLR7 and TLR9 ligands, R848 and CpGs, respectively. We found that IL-4 suppressed the gene expression of IFNβ and IFN-responsive genes (IRGs) upon TLR7 and TLR9 stimulation. IL-4 also inhibited IFN-dependent MHC Class I expression and amplification of IFN signaling pathways triggered upon TLR stimulation, as indicated by the suppression of IRF7 and STAT2. Moreover, IL-4 suppressed TLR7- and TLR9-induced cDC production of pro-inflammatory cytokines such as TNFα, IL-12p70 and IL-6 by inhibiting IFN-dependent and NFκB-dependent responses. IL-4 similarly suppressed TLR responses in splenic DCs. IL-4 inhibition of IRGs and pro-inflammatory cytokine production upon TLR7 and TLR9 stimulation was STAT6-dependent, since DCs from STAT6-KO mice were resistant to the IL-4 suppression. Analysis of SOCS molecules (SOCS1, -2 and -3) showed that IL-4 induces SOCS1 and SOCS2 in a STAT6 dependent manner and suggest that IL-4 suppression could be mediated by SOCS molecules, in particular SOCS2. IL-4 also decreased the IFN response and increased permissiveness to viral infection of cDCs exposed to a HIV-based lentivirus. Our results indicate that IL-4 modulates and counteracts pro-inflammatory stimulation induced by TLR7 and TLR9 and it may negatively affect responses against viruses and intracellular parasites.
Laboratory of Dendritic Cell Biology, Department of Microbiology and Immunology, Temple University, School of Medicine, Philadelphia, Pennsylvania, United States of America.
Uma
U
Sriram
Laboratory of Dendritic Cell Biology, Department of Microbiology and Immunology, Temple University, School of Medicine, Philadelphia, Pennsylvania, United States of America.
Jun
J
Xu
Laboratory of Dendritic Cell Biology, Department of Microbiology and Immunology, Temple University, School of Medicine, Philadelphia, Pennsylvania, United States of America.
Robert W
RW
Chain
Laboratory of Dendritic Cell Biology, Department of Microbiology and Immunology, Temple University, School of Medicine, Philadelphia, Pennsylvania, United States of America.
Linda
L
Varghese
Laboratory of Dendritic Cell Biology, Department of Microbiology and Immunology, Temple University, School of Medicine, Philadelphia, Pennsylvania, United States of America.
Marita
M
Chakhtoura
Joseph Stokes, Jr. Research Institute, Division of Rheumatology, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.
Heather L
HL
Bennett
Department of Surgery, The Children's Center for Fetal Research, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.
Philip W
PW
Zoltick
Laboratory of Dendritic Cell Biology, Department of Microbiology and Immunology, Temple University, School of Medicine, Philadelphia, Pennsylvania, United States of America.
Stefania
S
Gallucci
D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000821:virology; D005260:Female; D007093:Imidazoles / Q000494:pharmacology; D007113:Immunity, Innate; D050839:Interferon Regulatory Factor-7 / Q000235:genetics / Q000378:metabolism; D015847:Interleukin-4 / Q000502:physiology*; D015850:Interleukin-6 / Q000378:metabolism; D016180:Lentivirus Infections / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000819:agonists / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050795:STAT2 Transcription Factor / Q000235:genetics / Q000378:metabolism; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism; D051199:Toll-Like Receptor 7 / Q000819:agonists / Q000378:metabolism*; D051217:Toll-Like Receptor 9 / Q000378:metabolism*; D015533:Transcriptional Activation / Q000276:immunology; D014452:Ubiquitins / Q000235:genetics / Q000378:metabolism
D016207:Cytokines; C489550:G1p2 protein, mouse; D007093:Imidazoles; D050839:Interferon Regulatory Factor-7; D015850:Interleukin-6; C494235:Irf7 protein, mouse; D008562:Membrane Glycoproteins; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; C491590:Socs1 protein, mouse; C491409:Socs2 protein, mouse; C494080:Stat1 protein, mouse; C494085:Stat2 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C477038:Tlr7 protein, mouse; C495370:Tlr9 protein, mouse; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D014452:Ubiquitins; D015847:Interleukin-4; C402365:resiquimod