Interferon regulatory factor 3 is involved in Toll-like receptor 4 (TLR4)- and TLR3-induced IL-12p35 gene activation

Psoriasis is a chronic inflammatory skin disease affecting 2–3% of the world population and is mainly characterized by epidermal hyperplasia, scaling, and erythema. A prominent role for TNF in the pathogenesis of psoriasis has been shown, and consequently various types of TNF antagonists such as etanercept and infliximab have been used successfully. Recently, increasing amounts of data suggest that type I IFNs are also crucial mediators of psoriasis. To investigate whether blocking their respective receptors would be useful, TNFR1- and IFNAR1-deficient mice were challenged with Aldara, which contains imiquimod, and is used as an experimental model to induce psoriasis-like skin lesions in mice. Both transgenic mice showed partial protection toward Aldara-induced inflammation compared with control groups. Additionally, TNFR1 knockout mice showed sustained type I IFN production in response to Aldara. Double knockout mice lacking both receptors showed superior protection to Aldara in comparison with the single knockout mice and displayed reduced levels of IL-12p40, IL-17F, and S100A8, indicating that the TNF and type I IFN pathways contribute significantly to inflammation upon treatment with Aldara. Our findings reveal that dual inhibition of TNFR1 and IFNAR1 may represent a potential novel strategic treatment of psoriasis.

Section: Discussionmentioning

confidence: 99%

Dual Inhibition of TNFR1 and IFNAR1 in Imiquimod-Induced Psoriasiform Skin Inflammation in Mice

Grine

Dejager

Libert

et al. 2015

“…Human monocyte-derived DCs (moDCs) and murine bone marrow-derived DCs (BMDCs) were generated as previously described (17). The RAW 264.7 murine macrophage cell line and HEK-293 human kidney cell line were obtained from LGC Promochem.…”

Section: Cells and Reagentsmentioning

confidence: 99%

“…EMSAs were performed as previously described (17). For competition analysis, we used unlabeled ISRE from IFN-stimulated gene 15 (5Ј-GAT CCTCGGGAAAGGGAAACCGAAACTGAAGCC-3Ј), mutated ISRE from ISG15 (ISG15Mut; 5Ј-GATCCTCGGGAAAGGGAGGCCGAGGC TGAAGCC-3Ј), and NF-B consensus (5Ј-AGTTGAGGGACTTTCCCA GGC-3Ј).…”

Section: Emsasmentioning

confidence: 99%

IL-27 Synthesis Induced by TLR Ligation Critically Depends on IFN Regulatory Factor 3

Molle

Nguyen

Flamand

et al. 2007

Self Cite

141

119

IL-27 is a heterodimeric cytokine composed of EBV-induced gene 3 and p28. Produced by dendritic cells (DCs) in response to TLR ligands, IL-27 recently emerged as a key regulator of inflammatory responses. In this study, we first demonstrate that Toll/IL-1R-containing adaptor inducing IFN-β and its associated IFN regulatory factor (IRF) 3 transcription factor are critically involved in IL-27p28 expression in mouse DCs stimulated by TLR ligands. We then show that IL-27 serum levels are dramatically reduced in IRF3−/− upon LPS injection, indicating a critical role for IRF3 in TLR4-mediated IL-27 production in vivo. We identified an IRF3-binding site within the IL-27p28 promoter region which is required for IL-27p28 gene activation in reporter gene assays. In human DCs, IL-27p28 mRNA was preferentially induced by Toll/IL-1R-containing adaptor inducing IFN-β-coupled TLR ligands and following CMV infection. Furthermore, chromatin immunoprecipitation studies demonstrate that IRF3 is recruited to the endogenous p28 promoter in TLR4-stimulated human DCs. We conclude that IRF3 activation is a master switch for IL-27 synthesis.

“…IL12p35 expression is also tightly regulated both at the transcriptional and translational level (26,27). Specificity protein 1, AP-1, IRF-1, IRF-3, and IRF-8 have been described to play a role in the expression of human IL12A (23,28,29). RNA interference experiments showed a critical requirement for the NF-kB p50 subunit in the production of IL-12 by human monocyte-derived DCs (Mo-DCs) after CD40L and IL-1 stimulation (24).…”

mentioning

confidence: 99%

Mechanisms of IL-12 Synthesis by Human Dendritic Cells Treated with the Chemical Sensitizer NiSO4

Antonios

Rousseau

Larangé

et al. 2010

Allergic contact dermatitis, caused by metallic ions, is a T cell-mediated inflammatory skin disease. IL-12 is a 70-kDa heterodimeric protein composed of IL-12p40 and IL-12p35, playing a major role in the generation of allergen-specific T cell responses. Dendritic cells (DCs) are APCs involved in the induction of primary immune responses, as they possess the ability to stimulate naive T cells. In this study, we address the question whether the sensitizer nickel sulfate (NiSO4) itself or in synergy with other signals can induce the secretion of IL-12p70 in human monocyte-derived DCs (Mo-DCs). We found that IL-12p40 was produced by Mo-DC in response to NiSO4 stimulation. Addition of IFN-γ concomitantly to NiSO4 leads to IL-12p70 synthesis. NiSO4 treatment leads to the activation of MAPK, NF-κB pathways, and IFN regulatory factor 1 (IRF-1). We investigated the role of these signaling pathways in IL-12 production using known pharmacological inhibitors of MAPK and NF-κB pathways and RNA interference-mediated silencing of IRF-1. Our results showed that p38 MAPK, NF-κB, and IRF-1 were involved in IL-12p40 production induced by NiSO4. Moreover, IRF-1 silencing nearly totally abrogated IL-12p40 and IL-12p70 production provoked by NiSO4 and IFN-γ. In response to NiSO4, we observed that STAT-1 was phosphorylated on both serine and tyrosine residues and participated to NiSO4-induced IRF-1 activation. N-acetylcysteine abolished STAT-1 phosphorylation, suggesting that STAT-1 activation may be dependent on NiSO4-induced alteration of the redox status of the cell. These results indicate that p38 MAPK, NF-κB, and IRF-1 are activated by NiSO4 in Mo-DC and cooperate for IL-12 production.