The PDE4 inhibitor CHF6001 modulates pro-inflammatory cytokines, chemokines and Th1- and Th17-polarizing cytokines in human dendritic cells

Gianello, Veronica; Salvi, Valentina; Parola, Carmen; Moretto, Nadia; Facchinetti, Fabrizio; Civelli, Maurizio; Villetti, Gino; Bosisio, Daniela; Sozzani, Silvano

doi:10.1016/j.bcp.2019.03.006

Cited by 20 publications

(47 citation statements)

References 45 publications

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“…In a normal immune reaction, if external antigens flow in, antigen-presenting cells (APCs) will deliver antigens to helper T cells (Th cells) and induce differentiation to Th1, Th2, and Th17 [7,8]. Th1 cells secrete proinflammatory cytokine such as interferon gamma (IFNγ), tumor necrosis factor-alpha (TNF-α), IL-1α, IL-1β, IL-6, IL-8, and IL-23 [9]. In particular, IL-1α/β induces differentiation of keratin 6/16 protein by activating nuclear factor-kappa (NF-κB) signal transduction of Th1 cells [10].…”

Section: Introductionmentioning

confidence: 99%

Anti-inflammation activity of brazilin in TNF-α induced human psoriasis dermatitis skin model

Choi

Hwang

2019

Appl Biol Chem

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Psoriasis is a chronic inflammatory skin disease that causes erythema, scale, and invasion due to excessive proliferation of keratinocyte and vascular deformation of the upper part of the dermis. Recently, it has been reported that brazilin, an active compound of Caesalpinia sappan L., possesses anti-inflammatory activity in mouse macrophage. However, little is known about its effect or anti-inflammatory activity on psoriasis dermatitis. Thus, the objective of this study was to determine anti-inflammatory activity of brazilin in TNF-α-induced human keratinocyte (HaCaT) widely used as a model of psoriatic dermatitis. First, CCK-8 assay was performed to determine cytotoxicity of brazilin in HaCaT cells and cytotoxicity was not observed up to 7 μg/mL concentrations. Brazilin decreased mRNA expression levels of inflammatory cytokines such as IL-1α, IL-1β, IL-6, IL-8 and TNF-α in a concentration dependent manner. Brazilin also significantly reduced phosphorylation of I-κB, Akt, and MAPKs such as ERK, JNK, p38 and STAT3 in immortalized human keratinocytes (HaCaT) induced by TNF-α. In addition, inflammation causes the weakness of the skin barrier structure and increase cell permeability, stimulating serious problems in skin moisturizing. Thus, we observed changes of skin permeability in TNF-α induced inflammatory condition through transepithelial electrical resistance (TEER) assay. While TNF-α induced inflammation caused reduction of TEER value (ohm (Ω) × cm 2 ), it was recovered by treatment with brazilin in a concentration-dependent manner. These results strongly imply that brazilin can reinforce the skin barrier due to its anti-inflammatory activity. Therefore, brazilin could be a promising candidate for treating psoriasis dermatitis. which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

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Section: Introductionmentioning

confidence: 99%

Anti-inflammation activity of brazilin in TNF-α induced human psoriasis dermatitis skin model

Choi

Hwang

2019

Appl Biol Chem

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“…Activation of the cytotoxic activity of natural killer and CD8 + T cells protects against intracellular pathogens, but can also lead to tissue injury. DCs produce IL-23, and together with IL-6 and IL-1β, are involved in the expansion of Th17 cells, which are responsible for strong pro-inflammatory responses against extracellular pathogens, possibly leading to chronic inflammation and autoimmune diseases ( Gianello et al., 2019 ). Thus, for novel therapeutic strategies, it is important to focus on pathological conditions characterized by the expansion of Th1 and/or Th17 responses ( Gianello et al., 2019 ).…”

Section: Pathophysiology Of Armentioning

confidence: 99%

Phosphodiesterase 4 Inhibitors in Allergic Rhinitis/Rhinosinusitis

et al. 2020

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Allergic rhinitis/rhinosinusitis (AR) is the most common allergic disease. It affects patients’ quality of life and may influence the severity of lower airway disease such as asthma. Therefore, its treatment is of great importance. AR is treated by a combination of effective approaches; however, in some patients, the disease is uncontrolled. In the last several years, the concept of AR has shifted from increased T helper 2 (Th2) cell signaling and downstream inflammation to disease phenotypes with non-Th2-mediated inflammation. AR is a largely heterogenous group of airway diseases, and as such, research should not only focus on immunosuppressive agents (e.g., corticosteroids) but should also include targeted immunomodulatory pathways. Here, we provide an overview of novel therapies, focusing on the role of phosphodiesterase-4 (PDE4) inhibitors in AR. PDE4 inhibitors are potent anti-inflammatory agents that are used for the treatment of inflammatory airway diseases including AR. The PDE4 inhibitor roflumilast was shown to effectively control symptoms of AR in a randomized, placebo-controlled, double-blinded, crossover study in patients with a history of AR. However, only a few PDE4 inhibitors have proceeded to phase II and III clinical trials, due to insufficient clinical efficacy and adverse effects. Research is ongoing to develop more effective compounds with fewer side effects that target specific inflammatory pathways in disease pathogenesis and can provide more consistent benefit to patients with upper airway allergic diseases. Novel specific PDE4 inhibitors seem to fulfill these criteria.

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“…IL-12p70 promotes Th1 polarization when provided as signal 3 from the DC to a naive CD4 + T cell, whereas IL-1b in combination with IL-23 and IL-6 promotes Th17 polarization in na€ ıve human T-cells. 33 COL1A1 IL23A IL12A AC010422·6 CXCL1 IL6 IL12B CXCL2 IFNL1 IL1A CXCL3 DNAJC6 IL1B G0S2 MAP3K8 CCL3L3 KCNJ2 CXCL8 PTGS2 CCL3 PNRC1 BCL2A1 NFKBIZ IER3 IFNB1 TNF TNFAIP3 RIN2 INHBA CCL4 PTX3 CCL4L2 IRAK2 TNFAIP2 CDCA4 ADORA2A TRIP10 HS3ST3B1 TNFAIP6 IRF8 PTGER4 CPNE8 PMAIP1 NFKBIA SPRED2 PLAUR ICAM1 LTA CAMK1G HSPA1A SOCS3 FAM49A FAM60...…”

Section: Helminth Pcf Predominantly Suppresses Th1 and Th17 Programs mentioning

confidence: 99%

“…Different classes of pathogen-associated molecular patterns (PAMPs) induce different types of T helper cell responses, where effective responses to intracellular and virus-based PAMPs promote T helper type 1 (Th1), fungi and extracellular bacterial PAMPs promote T helper type 17 (Th17), and helminth parasites induce type 2 (Th2) responses. 1 Additionally, the influence of transforming growth factor-b during the interaction with the DC induces the differentiation of naive T helper cells towards Abbreviations: COX2, cyclooxygenase-2; DCs, dendritic cells; HSF1, heat shock factor 1; IFN-c, interferon-c; LPS, lipopolysaccharide; MyD88, myeloid differentiation primary response gene 88; PAMPs, pathogen-associated molecular patterns; PCF, pseudocoelomic fluid; PD-L1, programmed death-ligand 1; Rab7b, Ras related in brain 7b; Th1, type 1 helper; Th17, type 17 helper; Th2, type 2 helper; TLRs, Toll-like receptors; Treg, regulatory T cells; TSLP, thymic stromal lymphopoietin In addition to PAMPs, intestinal DCs can also sense specific endogenous signals originating from the intestinal epithelium in response to PAMP stimulation, including thymic stromal lymphopoietin (TSLP), interleukin-25 (IL-25) and IL- 33. TSLP has been reported to influence DCs to promote Th2 responses, 4 and IL-33 seems to further strengthen TSLP-DC-mediated Th2 responses 5 as well as inducing Treg cell immune responses.…”

Section: Introductionmentioning

confidence: 99%

“…IL-12p70 promotes Th1 polarization when provided as signal 3 from the DC to a naive CD4 + T cell, whereas IL-1b in combination with IL-23 and IL-6 promotes Th17 polarization in na€ ıve human T-cells 33. (a) Overview of study design: (i) isolation of CD14 + monocytes from human blood peripheral blood mononuclear cells, (ii) differentiation of monocytes into dendritic cells (moDCs) using recombinant human IL-4 and granulocyte-macrophage colony-stimulating factor (GM-CSF) for 6 days, (iii) stimulation of moDCs with indicated compounds (1), (iv) collection and preparation of samples for RNA-seq, flow cytometry and ELISA analyses.…”

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Body fluid from the parasitic worm Ascaris suum inhibits broad‐acting pro‐inflammatory programs in dendritic cells

et al. 2019

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Dendritic cells (DCs) are essential for generating T-cell-based immune responses through sensing of potential inflammatory and metabolic cues in the local environment. However, there is still limited insight into the processes defining the resultant DC phenotype, including the type of early transcriptional changes in pro-inflammatory cues towards regulatory or type 2 immune-based cues induced by a variety of exogenous and endogenous molecules. Here we compared the ability of a selected number of molecules to modulate the pro-inflammatory phenotype of lipopolysaccharide (LPS) and interferon-c (IFN-c)-stimulated human monocytederived DCs towards an anti-inflammatory or regulatory phenotype, including Ascaris suum body fluid [helminth pseudocoelomic fluid (PCF)], the metabolites succinate and butyrate, and the type 2 cytokines thymic stromal lymphopoietin and interleukin-25. Our data show that helminth PCF and butyrate treatment suppress the T helper type 1 (Th1)inducing pro-inflammatory DC phenotype through induction of different transcriptional programs in DCs. RNA sequencing indicated that helminth PCF treatment strongly inhibited the Th1 and Th17 polarizing ability of LPS + IFN-c-matured DCs by down-regulating myeloid differentiation primary response gene 88 (MyD88)-dependent and MyD88-independent pathways in Toll-like receptor 4 signaling. By contrast, butyrate treatment had a strong Th1-inhibiting action, and transcripts encoding important gut barrier defending factors such as IL18, IL1B and CXCL8 were up-regulated. Collectively, our results further understanding of how compounds from parasites and gut microbiota-derived butyrate may exert immunomodulatory effects on the host immune system.

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The PDE4 inhibitor CHF6001 modulates pro-inflammatory cytokines, chemokines and Th1- and Th17-polarizing cytokines in human dendritic cells

Cited by 20 publications

References 45 publications

Anti-inflammation activity of brazilin in TNF-α induced human psoriasis dermatitis skin model

Anti-inflammation activity of brazilin in TNF-α induced human psoriasis dermatitis skin model

Phosphodiesterase 4 Inhibitors in Allergic Rhinitis/Rhinosinusitis

Body fluid from the parasitic worm Ascaris suum inhibits broad‐acting pro‐inflammatory programs in dendritic cells

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