Induction of tolerogenic lung CD4+ T cells by local treatment with a pSTAT-3 and pSTAT-5 inhibitor ameliorated experimental allergic asthma.
Signal transducer and activator of transcription (STAT)-3 inhibitors play an important role in regulating immune responses. Galiellalactone (GL) is a fungal secondary metabolite known to interfere with the binding of phosphorylated signal transducer and activator of transcription (pSTAT)-3 as well of pSTAT-6 dimers to their target DNA in vitro. Intra nasal delivery of 50 μg GL into the lung of naive Balb/c mice induced FoxP3 expression locally and IL-10 production and IL-12p40 in RNA expression in the airways in vivo. In a murine model of allergic asthma, GL significantly suppressed the cardinal features of asthma, such as airway hyperresponsiveness, eosinophilia and mucus production, after sensitization and subsequent challenge with ovalbumin (OVA). These changes resulted in induction of IL-12p70 and IL-10 production by lung CD11c(+) dendritic cells (DCs) accompanied by an increase of IL-3 receptor α chain and indoleamine-2,3-dioxygenase expression in these cells. Furthermore, GL inhibited IL-4 production in T-bet-deficient CD4(+) T cells and down-regulated the suppressor of cytokine signaling-3 (SOCS-3), also in the absence of STAT-3 in T cells, in the lung in a murine model of asthma. In addition, we found reduced amounts of pSTAT-5 in the lung of GL-treated mice that correlated with decreased release of IL-2 by lung OVA-specific CD4(+) T cells after treatment with GL in vitro also in the absence of T-bet. Thus, GL treatment in vivo and in vitro emerges as a novel therapeutic approach for allergic asthma by modulating lung DC phenotype and function resulting in a protective response via CD4(+)FoxP3(+) regulatory T cells locally.
Laboratory of Cellular and Molecular Immunology of Lung, Institute of Molecular Medicine, Universitätsmedizin Mainz, 55131 Mainz, Germany.
Michael
M
Hausding
Marcus
M
Tepe
Caroline
C
Ubel
Hans A
HA
Lehr
Bernd
B
Röhrig
Yvonne
Y
Höhn
Andrea
A
Pautz
Tatjana
T
Eigenbrod
Timm
T
Anke
Hartmut
H
Kleinert
Gerhard
G
Erkel
Susetta
S
Finotto
D000281:Administration, Intranasal; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology; D039521:CD11c Antigen / Q000378:metabolism; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005260:Female; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism; D015847:Interleukin-4 / Q000096:biosynthesis; D007783:Lactones / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D008168:Lung / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D016185:Receptors, Interleukin-3 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors*; D050799:STAT5 Transcription Factor / Q000037:antagonists & inhibitors*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology; D000098815:T-bet Transcription Factor
D018927:Anti-Asthmatic Agents; D039521:CD11c Antigen; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007783:Lactones; D016185:Receptors, Interleukin-3; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; C491411:Socs3 protein, mouse; C494087:Stat3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; C416043:galiellalactone; D015847:Interleukin-4