Induces IL-23 Expression Research Articles

Artesunate alleviates psoriasis-like dermatitis by reducing interleukin-23 expression in tumor necrosis factor-alpha-induced HaCaT cells.

Artesunate (ART), an antimalarial drug with a multifunctional immunomodulatory effect, reduces psoriasis disease. ART can alleviate psoriasis-like dermatitis in mice but has no effect on proinflammatory cytokines in the blood. Thus, we hypothesized that the skin might be the target tissue of ART during the treatment of psoriasis. The interleukin (IL)-23/IL-17 axis has a key role in the pathogenesis of psoriasis. However, whether and how ART manipulates the IL-23 signal during psoriasis is unknown. This study found that IL-23 is highly expressed in the epidermis of psoriasis lesions and positively correlated with histological neutrophil infiltration and clinical psoriasis area and severity index (PASI)scores. Furthermore, ART inhibits the migration and cell cycle, as well as tumor necrosis factor-alpha (TNF-α)-induced IL-23 expression in HaCaT cells in a dose-dependent manner, probably through interference with the nuclear factor kappa B (NF-κB) signalling pathway. Animal experiments in imiquimod (IMQ)-induced psoriasis-like mice model also suggested that ART dose-dependently reduces IL-23 in the epidermis and ameliorates neutrophil infiltration. These findings thus provide further molecular evidence supporting ART as a promising drug for psoriasis in clinic.

Interaction of Nrf2 with dimeric STAT3 induces IL-23 expression: Implications for breast cancer progression.

Persistent activation of STAT3 and Nrf2 is considered to stimulate the aggressive behavior of basal-like breast cancer (BLBC). However, the precise mechanism underlying sustained overactivation of these transcription factors and their roles in breast cancer progression remain elusive. Analysis of the TCGA multi-omics data showed that high levels of STAT3 and Nrf2 mRNA were correlated with elevated expression of P-STAT3Y705 and Nrf2 target proteins in breast cancer patients. Our present study demonstrates a unique interaction between Nrf2 and STAT3 in the maintenance and progression of BLBC. RNA sequencing analysis identified the gene encoding IL-23A upregulated by concurrent binding of STAT3 and Nrf2 to its promoter. IL-23A depletion also showed the similar phenotypic changes to those caused by double knockdown of both transcription factors. In conclusion, the STAT3-Nrf2 interaction accelerates BLBC growth and progression by augmenting IL-23A expression, which underscores the importance of subtype-specific molecular pathways in human breast cancer.

Cervical Cancer-Instructed Stromal Fibroblasts Enhance IL23 Expression in Dendritic Cells to Support Expansion of Th17 Cells.

Persistent infection with high-risk human papillomavirus (HPV) is a prerequisite for the development of cervical cancer. HPV-transformed cells actively instruct their microenvironment, promoting chronic inflammation and cancer progression. We previously demonstrated that cervical cancer cells contribute to Th17 cell recruitment, a cell type with protumorigenic properties. In this study, we analyzed the expression of the Th17-promoting cytokine IL23 in the cervical cancer micromilieu and found CD83+ mature dendritic cells (mDC) coexpressing IL23 in the stroma of cervical squamous cell carcinomas in situ. This expression of IL23 correlated with stromal Th17 cells, advanced tumor stage, lymph node metastasis, and cervical cancer recurrence. Cocultures of cervical cancer-instructed mDCs and cervical fibroblasts led to potent protumorigenic expansion of Th17 cells in vitro but failed to induce antitumor Th1 differentiation. Correspondingly, cervical cancer-instructed fibroblasts increased IL23 production in cocultured cervical cancer-instructed mDCs, which mediated subsequent Th17 cell expansion. In contrast, production of the Th1-polarizing cytokine IL12 in the cancer-instructed mDCs was strongly reduced. This differential IL23 and IL12 regulation was the consequence of an increased expression of the IL23 subunits IL23p19 and IL12p40 but decreased expression of the IL12 subunit IL12p35 in cervical cancer-instructed mDCs. Cervical cancer cell-derived IL6 directly suppressed IL12p35 in mDCs but indirectly induced IL23 expression in fibroblast-primed mDCs via CAAT/enhancer-binding protein β (C/EBPβ)-dependent induction of IL1β. In summary, our study defines a mechanism by which the cervical cancer micromilieu supports IL23-mediated Th17 expansion associated with cancer progression. SIGNIFICANCE: Cervical cancer cells differentially regulate IL23 and IL12 in DC fibroblast cocultures in an IL6/C/EBPβ/IL1β-dependent manner, thereby supporting the expansion of Th17 cells during cancer progression.

Oxidized Low-Density Lipoprotein-Deteriorated Psoriasis Is Associated with the Upregulation of Lox-1 Receptor and Il-23 Expression In Vivo and In Vitro.

Psoriasis is a chronic inflammatory skin disease. Even though scientists predict that abnormalities in lipid metabolism play an important role in the pathogenesis of psoriasis, the actual underlying mechanisms are still unclear. Therefore, understanding the possible relationship between mechanisms of the occurrence of psoriasis and dyslipidemia is an important issue that may lead to the development of effective therapies. Under this principle, we investigated the influences of hyperlipidemia in imiquimod (IMQ)-induced psoriasis-like B6.129S2-Apoetm1Unc/J mice and oxidized low-density lipoprotein (oxLDL) in tumor necrosis factor (TNF)-α-stimulated Hacat cells. In our study, we showed that a high-cholesterol diet aggravated psoriasis-like phenomena in IMQ-treated B6.129S2-Apoetm1Unc/J mice. In vitro analysis showed that oxLDL increased keratinocyte migration and lectin-type oxLDL receptor 1 (LOX-1) expression. Evidence suggested that interleukin (IL)-23 was a main cytokine in the pathogenesis of psoriasis. High-cholesterol diet aggravated IL-23 expression in IMQ-treated B6.129S2-Apoetm1Unc/J mice, and oxLDL induced IL-23 expression mediated by LOX-1 in TNF-α-stimulated Hacat cells. Therefore, it will be interesting to investigate the factors for the oxLDL induction of LOX-1 in psoriasis. LOX-1 receptor expression may be another novel treatment option for psoriasis and might represent the most promising strategy.

Butyrate increases IL-23 production by stimulated dendritic cells

The gut microbiota is essential for the maintenance of intestinal immune homeostasis and is responsible for breaking down dietary fiber into short-chain fatty acids (SCFAs). Butyrate, the most abundant bioactive SCFA in the gut, is a histone deacetylase inhibitor (HDACi), a class of drug that has potent immunomodulatory properties. This characteristic of butyrate, along with our previous discovery that conventional dendritic cells (DCs) are required for the development of experimental colitis, led us to speculate that butyrate may modulate DC function to regulate gut mucosal homeostasis. We found that butyrate, in addition to suppressing LPS-induced bone marrow-derived DC maturation and inhibiting DC IL-12 production, significantly induced IL-23 expression. The upregulation of mRNA subunit IL-23p19 at the pretranslational level was consistent with the role of HDACi on the epigenetic modification of gene expression. Furthermore, the mechanism of IL-23p19 upregulation was independent of Stat3 and ZBP89. Coculture of splenocytes with LPS-stimulated DCs pretreated with or without butyrate was performed and showed a significant induction of IL-17 and IL-10. We demonstrated further the effect of butyrate in vivo using dextran sulfate sodium (DSS)-induced colitis and found that the addition of butyrate in the drinking water of mice worsened DSS-colitis. This is in contrast to the daily intraperitoneal butyrate injection of DSS-treated mice, which mildly improved disease severity. Our study highlights a novel effect of butyrate in upregulating IL-23 production of activated DCs and demonstrates a difference in the host response to the oral vs. systemic route of butyrate administration.

Mechanical Skin Injury Induces TLR4/MyD88 Dependent IL-23 Expression In Epidermal Keratinocytes

RationaleScratching and epidermal hyperplasia are hallmarks of atopic dermatitis. IL-23 is a cytokine that induces epidermal hyperplasia. We examined the hypothesis that mechanical skin injury by tape stripping, a surrogate of scratching, induces IL-23 expression in the skin.MethodsEar skin of mice was tape stripped then examined 6 hrs later for IL-23 expression by quantitative RT-PCR and immunohistochemistry. Low molecular weight hyaluronic acid (HA) was injected intradermally, and 3 hrs later, skin was harvested. Langerhans cells were depleted by i.p. injection of 1 μg diphtheria toxin (DT) into langerin-eGFP-DTR mice, and 24 hrs later ear skin was tape stripped then harvested. The keratinocyte cell line, PAM212 cells was treated with HA (50 μg/ml) for 3hResultsTape stripping induced epidermal IL-23 expression of WT, but not TLR4 and MyD88 deficient mice. IL-23 induction by tape stripping in germ free mice was comparable to that in specific pathogen free mice. Skin of LC-depleted mice showed the same level of IL-23 induction compared to intact mice. Intradermal injection of the endogenous danger signal molecule, HA induced IL-23 expression in the skin of WT, but not TLR4 deficient mice. HA treatment induced IL-23 expression by PAM212 cells in vitro.ConclusionScratching may contribute to epidermal hyperplasia in AD through the release of the endogenous danger signal molecule HA, which directly induces IL-23 expression from keratinocytes through TLR4/MyD88 signaling. RationaleScratching and epidermal hyperplasia are hallmarks of atopic dermatitis. IL-23 is a cytokine that induces epidermal hyperplasia. We examined the hypothesis that mechanical skin injury by tape stripping, a surrogate of scratching, induces IL-23 expression in the skin. Scratching and epidermal hyperplasia are hallmarks of atopic dermatitis. IL-23 is a cytokine that induces epidermal hyperplasia. We examined the hypothesis that mechanical skin injury by tape stripping, a surrogate of scratching, induces IL-23 expression in the skin. MethodsEar skin of mice was tape stripped then examined 6 hrs later for IL-23 expression by quantitative RT-PCR and immunohistochemistry. Low molecular weight hyaluronic acid (HA) was injected intradermally, and 3 hrs later, skin was harvested. Langerhans cells were depleted by i.p. injection of 1 μg diphtheria toxin (DT) into langerin-eGFP-DTR mice, and 24 hrs later ear skin was tape stripped then harvested. The keratinocyte cell line, PAM212 cells was treated with HA (50 μg/ml) for 3h Ear skin of mice was tape stripped then examined 6 hrs later for IL-23 expression by quantitative RT-PCR and immunohistochemistry. Low molecular weight hyaluronic acid (HA) was injected intradermally, and 3 hrs later, skin was harvested. Langerhans cells were depleted by i.p. injection of 1 μg diphtheria toxin (DT) into langerin-eGFP-DTR mice, and 24 hrs later ear skin was tape stripped then harvested. The keratinocyte cell line, PAM212 cells was treated with HA (50 μg/ml) for 3h ResultsTape stripping induced epidermal IL-23 expression of WT, but not TLR4 and MyD88 deficient mice. IL-23 induction by tape stripping in germ free mice was comparable to that in specific pathogen free mice. Skin of LC-depleted mice showed the same level of IL-23 induction compared to intact mice. Intradermal injection of the endogenous danger signal molecule, HA induced IL-23 expression in the skin of WT, but not TLR4 deficient mice. HA treatment induced IL-23 expression by PAM212 cells in vitro. Tape stripping induced epidermal IL-23 expression of WT, but not TLR4 and MyD88 deficient mice. IL-23 induction by tape stripping in germ free mice was comparable to that in specific pathogen free mice. Skin of LC-depleted mice showed the same level of IL-23 induction compared to intact mice. Intradermal injection of the endogenous danger signal molecule, HA induced IL-23 expression in the skin of WT, but not TLR4 deficient mice. HA treatment induced IL-23 expression by PAM212 cells in vitro. ConclusionScratching may contribute to epidermal hyperplasia in AD through the release of the endogenous danger signal molecule HA, which directly induces IL-23 expression from keratinocytes through TLR4/MyD88 signaling. Scratching may contribute to epidermal hyperplasia in AD through the release of the endogenous danger signal molecule HA, which directly induces IL-23 expression from keratinocytes through TLR4/MyD88 signaling.

Upregulation of IL-23 Expression in Patients with Chronic Hepatitis B Is Mediated by the HBx/ERK/NF-κB Pathway

IL-23 is a newly discovered proinflammatory cytokine that contributes to the maintenance and expansion of Th17 cells. IL-23 has recently been identified as playing a critical role in a number of chronic inflammatory diseases. However, the regulatory mechanism of IL-23 in chronic hepatitis B (CHB) remains largely unknown. The aims of this study were to detect the expression of IL-23 in CHB patients and to explore the molecular mechanism of hepatitis B virus (HBV)-induced IL-23 expression. Serum levels and hepatic expression of IL-23 were significantly upregulated in CHB patients. A positive correlation was found between IL-23 expression and the histological activity index score, HBV DNA load, and serum alanine aminotransferase and aspartate aminotransferase levels. HBx protein increased IL-23 expression in a dose-dependent manner. It also aided in the nuclear translocation of NF-κB, which directly bound to the promoters of IL-23 subunits p19 and p40 to facilitate their transcription. NF-κB inhibitors blocked the effect of HBx on IL-23 induction, and NF-κB subunits p65 and p50 increased the augmented IL-23 expression. Inhibition of ERK1/2 activation and transfection with ERK dominant-negative plasmid significantly blocked the HBx-induced IL-23 expression. Furthermore, PI3K and Ras-MEK-MAPK inhibitors significantly decreased the ERK1/2 activation and IL-23 expression. Thus, we report a new molecular mechanism for HBV-induced IL-23 expression, which involves the activation of the ERK/NF-κB pathway by HBx, leading to the transactivation of the IL-23 p19 and p40 promoters.

VEGF Induces IL-23 Expression in Keratinocytes through p38 Signaling

Background: Psoriasis is a chronic inflammatory skin disorder which is associated with increased cutaneous vascular endothelial growth factor (VEGF) expression. Several studies demonstrate that VEGF plays an important role in psoriasis pathogenesis by linking angiogenesis and inflammation. We aimed to study the molecular functions of VEGF in psoriasis and dissect a link between VEGF and pro-inflammatory cytokine expression in human keratinocytes. Methods: VEGF expression was evaluated in sections from lesional psoriatic skin by immunohistochemistry. Cultured keratinocytes were transfected with a VEGF expression plasmid and changes in pro-inflammatory cytokine expression were investigated by qPCR, ELISA and dot-blot. Protein phosphorylation profiles in lysates from cells overexpressing VEGF were analysed to identify the underlying signaling pathways. Specific inhibitors or siRNA knockdown were used in confirmatory experiments. Results: In lesional psoriatic skin, VEGF and the pro-inflammatory cytokine IL-23 are both strongly expressed by epidermal keratinocytes. VEGF over-expression in cultured keratinocytes resulted in increased IL-23 and IL-6 mRNA transcript abundance and protein expression. At the same time VEGF over-expression strongly increased phosphorylation of p38 MAPK, CREB and HSp27. Inhibition of p38 MAPK by SB203580 blocked VEGF induced IL-23 expression while siRNA mediated knockdown of CREB or HSp27 showed no effect. Conclusions: VEGF up-regulates pro-inflammatory IL-23 and IL-6 secretion through p38 MAPK in epidermal keratinocytes in psoriasis. Targeting VEGF and/or p38 MAPK could lead to novel anti-inflammatory treatments for this chronic skin disease.

IFN-γ induces IL-23 expression in primary human monocytes via the p38 mitogen activated protein kinase independently of the JAK/STAT signalling

IFN-γ induces IL-23 expression in primary human monocytes via the p38 mitogen activated protein kinase independently of the JAK/STAT signalling