Inhibition of IL-17 and IL-23 in Human Keratinocytes by the A3 Adenosine Receptor Agonist Piclidenoson

Cohen, Shira; Barer, Faina; Itzhak, Inbal; Silverman, Michael H.; Fishman, Pnina

doi:10.1155/2018/2310970

Cited by 30 publications

(22 citation statements)

References 28 publications

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“…The effects of IB-MECA, a selective agonist of A 3 AR, were evaluated in a psoriasis model of human keratinocytes (HaCat) cells. IB-MECA induced inhibition of interleukin 17 and interleukin 23 expression levels, mediated via NF-κB downregulation and inhibition of TNF-α 51…”

Section: A3ar Agonists Inhibit Inflammatory Cytokine Productionmentioning

confidence: 92%

Targeting the A3 adenosine receptor to treat cytokine release syndrome in cancer immunotherapy

Cohen

Fishman

2019

DDDT

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Cancer patients undergoing immunotherapy may develop cytokine release syndrome (CRS), an inflammatory cytokine storm condition, followed by neurotoxic manifestations and may be life-threatening. The current treatments for CRS successfully reduce the inflammatory response but may limit the anticancer effect of the given immunotherapy and fail to overcome the neurotoxic adverse events. Adenosine, a ubiquitous purine nucleoside, induces a plethora of effects in the body via its binding to four adenosine receptors A 1 , A 2a , A 2b , and the A 3. Highly selective agonists to the A 3 adenosine receptor act as inhibitors of proinflammatory cytokines, possess robust anti-inflammatory and anticancer activity, and concomitantly, induce neuroprotective effects. Piclidenoson and namodenoson belong to this group of compounds, are effective upon oral administration, show an excellent safety profile in human clinical studies, and therefore, may be considered as drug candidates to treat CRS. In this article, the detailed anti-inflammatory characteristics of these compounds and the rationale to use them as drugs to combat CRS are described.

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Section: A3ar Agonists Inhibit Inflammatory Cytokine Productionmentioning

confidence: 92%

Targeting the A3 adenosine receptor to treat cytokine release syndrome in cancer immunotherapy

Cohen

Fishman

2019

DDDT

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“…These and other observations led to investigations that utilize topical application of AdoR agonists for the treatment of psoriasis. Indeed, engagement of the AdoR A 3 leads to reduced production of IL-17 and IL-23 in KCs of psoriatic patients, inducing amelioration of the disease ( 32 , 33 ). Therefore, several drugs acting as agonist for different types of AdoR are currently used in clinical trials of skin- and other inflammatory diseases ( 34 , 35 ).…”

Section: Adenosine Triphosphate (Atp) In Peripheral Tissuesmentioning

confidence: 99%

ATP and Its Metabolite Adenosine as Regulators of Dendritic Cell Activity

2018

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Adenosine (Ado) is a well-studied neurotransmitter, but it also exerts profound immune regulatory functions. Ado can (i) actively be released by various cells into the tissue environment and can (ii) be produced through the degradation of extracellular ATP by the concerted action of CD39 and CD73. In this sequence of events, the ectoenzyme CD39 degrades ATP into ADP and AMP, respectively, and CD73 catalyzes the last step leading to the production of Ado. Extracellular ATP acts as a “danger” signal and stimulates immune responses, i.e. by inflammasome activation. Its degradation product Ado on the other hand acts rather anti-inflammatory, as it down regulates functions of dendritic cells (DCs) and dampens T cell activation and cytokine secretion. Thus, the balance of proinflammatory ATP and anti-inflammatory Ado that is regulated by CD39+/CD73+ immune cells, is important for decision making on whether tolerance or immunity ensues. DCs express both ectoenzymes, enabling them to produce Ado from extracellular ATP by activity of CD73 and CD39 and thus allow dampening of the proinflammatory activity of adjacent leukocytes in the tissue. On the other hand, as most DCs express at least one out of four so far known Ado receptors (AdoR), DC derived Ado can also act back onto the DCs in an autocrine manner. This leads to suppression of DC functions that are normally involved in stimulating immune responses. Moreover, ATP and Ado production thereof acts as “find me” signal that guides cellular interactions of leukocytes during immune responses. In this review we will state the means by which Ado producing DCs are able to suppress immune responses and how extracellular Ado conditions DCs for their tolerizing properties.

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“…Th17 cells are defined by the expression of ROR transcription factors and secretion of Th17 cytokines [10,11]. Non-Th17 sources of Th17 cytokines have been described and include CD4+ T cells, neutrophils, Paneth cells, Tregs (Foxp3+ and Foxp3-), Foxp3+IL-17A T cells, rTh17 cells (Foxp3-IL-17A+IL-10+ Th cells), γδ T cells, CD8+ T cells (TC17, TNC17), macrophages, natural killer cells, mast cells, neutrophils, polymorphonuclear cells, keratinocytes, and fibroblasts, though more sources are being regularly described [11,40,41,42,43,44,45,46].…”

Section: Expected Resultsmentioning

confidence: 99%

Induction of a Th17 Phenotype in Human Skin—A Mimic of Dermal Inflammatory Diseases

Garrett

Zhao

Feghali‐Bostwick

2019

MPs

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Th17 cells are a subset of effector T helper cells that produce interleukin (IL)-17A, IL-17F, IL-22, and IL-26, which can promote tissue inflammation and contribute to the pathogenesis of rheumatic, fibrosing, and other diseases. Research into these diseases is often limited by a lack of an animal model that closely mimics human disease and the paucity of patient clinical tissues. Therefore, the development of relevant experimental models is crucial. Three media formulations of Th17-skewing cocktail (CT) were evaluated for the ability to induce a Th17 signature in an ex vivo human skin model: CT9 contained αCD3, αCD28, IL-23, IL-1β, IFNγ, IL-4, IL-6, IL-21, and TGFβ; CT8 lacked IL-1β; and CT4 only contained αCD3, αCD28, IL-23, and IL-1β. Healthy donor skin was defatted, distributed as 3 mm punch biopsies, and incubated with one of the cocktail formulations or vehicle for 48 h. All of the cocktail formulations independently significantly stimulated the expression of each gene examined. CT4 induced IL-17A expression 1024-fold, significantly higher than CT9 and CT8. IL-17F was robustly stimulated by CT4 (1557-fold), CT9 (622-fold), and CT8 (111-fold), with significant differences between the CT groups. All of the formulations significantly induced IL-22 (16–42-fold). CT9 stimulated the highest IL-26 response (41-fold), which was significantly higher than CT4 and CT8. IL-10 was stimulated significantly higher with CT8 (10-fold) than CT4 or CT9. The secretion of IL-17A was significantly elevated with all cocktail formulations. Robust IL-17A/IL-17F cytokine induction was preferentially mediated by CT4, which suggested that its components are the minimal constituents necessary for the full induction of these genes in this human skin explant model, while the downstream cytokines were preferentially upregulated by CT4 (IL-22), CT9 (IL-26), or CT8 (IL-10). In summary, our findings suggest that the induction of a Th17 phenotype in human skin is feasible and can be used as a model for rheumatic and fibrosing diseases where Th17 skewing is observed.

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Inhibition of IL-17 and IL-23 in Human Keratinocytes by the A₃ Adenosine Receptor Agonist Piclidenoson

Cited by 30 publications

References 28 publications

<p>Targeting the A<sub>3</sub> adenosine receptor to treat cytokine release syndrome in cancer immunotherapy</p>

<p>Targeting the A<sub>3</sub> adenosine receptor to treat cytokine release syndrome in cancer immunotherapy</p>

ATP and Its Metabolite Adenosine as Regulators of Dendritic Cell Activity

Induction of a Th17 Phenotype in Human Skin—A Mimic of Dermal Inflammatory Diseases

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