HSP70-Homolog DnaK of <i>Pseudomonas aeruginosa</i> Increases the Production of IL-27 through Expression of <i>EBI3</i> via TLR4-Dependent NF-κB and TLR4-Independent Akt Signaling
IL-27, a heterodimeric cytokine composed of the p28 subunit and Epstein–Barr virus-induced gene 3 (EBI3), acts as a potent immunosuppressant and thus limits pathogenic inflammatory responses. IL-27 is upregulated upon <i>Pseudomonas aeruginosa</i> infection in septic mice, increasing sus...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-12-01
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| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/21/23/9194 |
| Summary: | IL-27, a heterodimeric cytokine composed of the p28 subunit and Epstein–Barr virus-induced gene 3 (EBI3), acts as a potent immunosuppressant and thus limits pathogenic inflammatory responses. IL-27 is upregulated upon <i>Pseudomonas aeruginosa</i> infection in septic mice, increasing susceptibility to the infection and decreasing clearance of the pathogen. However, it remains unclear which <i>P. aeruginosa</i>-derived molecules promote production of IL-27. In this study, we explored the mechanism by which <i>P. aeruginosa</i> DnaK, a heat shock protein 70-like protein, induces <i>EBI3</i> expression, thereby promoting production of IL-27. Upregulation of <i>EBI3</i> expression did not lead to an increase in IL-35, which consists of the p35 subunit and EBI3. The IL-27 production in response to DnaK was biologically active, as reflected by stimulation of IL-10 production. DnaK-mediated expression of <i>EBI3</i> was driven by two distinct signaling pathways, NF-κB and Akt. However, NF-κB is linked to TLR4-associated signaling pathways, whereas Akt is not. Taken together, our results reveal that <i>P. aeruginosa</i> DnaK potently upregulates <i>EBI3</i> expression, which in turn drives production of the prominent anti-inflammatory cytokine IL-27, as a consequence of TLR4-dependent activation of NF-κB and TLR4-independent activation of the Akt signaling pathway. |
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| ISSN: | 1661-6596 1422-0067 |