Cancer and Autoimmune Diseases as Two Sides of Chronic Inflammation and the Method of Therapy.

Chronic inflammation is associated with a prolonged increase in various inflammatory factors. According to clinical data, it can be linked with both cancer and autoimmune diseases in the same patients. This raises the critical question of how chronic inflammation relates to seemingly opposing diseases - tumors, in which there is immunosuppression, and autoimmune diseases, in which there is over-activation of the immune system. In this review, we consider chronic inflammation as a prerequisite for both immune suppression and an increased likelihood of autoimmune damage. We also discuss potential disease-modifying therapies targeting chronic inflammation, which can be helpful for both cancer and autoimmunity. On the one hand, pro-inflammatory factors persisting in the areas of chronic inflammation stimulate the production of anti-inflammatory factors due to a negative feedback loop, eliciting immune suppression. On the other hand, chronic inflammation can bring the baseline immunity closer to the threshold level required for triggering an autoimmune response using the bystander activation of immune cells. Focusing on the role of chronic inflammation in cancer and autoimmune diseases may open prospects for more intensive drug discovery for chronic inflammation.

The Therapeutic Potential of Urolithin A for Cancer Treatment and Prevention.

BACKGROUND: Urolithin A is the metabolite of natural polyphenol ellagic acid and ellagitannins generated by gut microbiota. Urolithin A is better absorbed in the gastrointestinal tract than its parent substances. Thus, the variable effects of ellagitannin-reach food (like pomegranate fruit, walnuts, tea, and others) on people's health might be linked with the differences in individual microbiota content. Urolithin A possesses various anti-inflammatory and anti-cancer effects, as shown by in vivo and in vitro studies. OBJECTIVES: In the current review, we consider anti-inflammatory and direct anti-cancer urolithin A effects as well as their molecular mechanisms, which might be the basement of clinical trials, estimating urolithin A anti-cancer effects. CONCLUSION: Urolithin A attenuated the pro-inflammatory factors production (IL-6, IL-1ß, NOS2 and others) in vitro studies. Oral urolithin A treatment caused prominent anti-cancer and anti-inflammatory action in various in vivo studies, including colitis rat model, carrageenan-induced paw edema mice model, models of pancreatic cancer, and models of obesity. The main molecular mechanisms of these effects might be the modulation of aryl hydrocarbon receptors, which antagonism may lead to decreasing of chronic inflammation. Other primary targets of urolithin A might be the processes of protein phosphorylation (for instance, it decreases the phosphorylation of protein kinase B) and p53 stabilization. Anti-inflammatory effects of urolithin A can be reached in physiologically relevant concentrations. This might be of vital importance for preventing immune suppression associated with chronic inflammation in cancer. Considering the favorable urolithin A safety profile, it is a promising compound for cancer treatment and prevention.

Polyphenols as the Potential Disease-modifying Therapy in Cancer.

BACKGROUND: Disease-modifying therapy in cancer can be defined as long-term treatment that has a beneficial outcome on the course of cancer, affecting the underlying pathophysiology of cancer. The anticancer potential of polyphenols is widely studied. However, there is a significant gap between experimental data obtained in vitro and in vitro and the current role of polyphenols in cancer therapy. OBJECTIVE: In this article, the reason for this inconsistency is discussed, which might be in the design of polyphenols clinical trials. The approach of long-term polyphenol disease-modifying therapy in cancer is encouraged. CONCLUSION: The physiologic concentrations of polyphenols are not sufficient for reaching cytotoxic levels. Therefore, the immune modulation and effects on cancer signal transduction pathways should be considered in the design of polyphenol clinical trials. Such effects apparently can not cause the rapid regression of the disease. However, more likely, they can modulate the course of the disease, leading to favorable changes in the patient's condition in case of long-term treatment..

The Dual Role of the ß2-Adrenoreceptor in the Modulation of IL-17 and IFN-γ Production by T Cells in Multiple Sclerosis.

Norepinephrine is a neurotransmitter that also has an immunomodulatory effect and is involved in multiple sclerosis (MS) pathogenesis. This study aimed to clarify the role of the ß2-adrenoreceptor in the norepinephrine-mediated modulation of interleukin-17 (IL-17) and interferon-γ (IFN-γ) production, which play a critical pathogenetic role in MS. CD4+ T cells obtained from twenty-five relapsing-remitting MS patients and sixteen healthy subjects were cultured ex vivo with norepinephrine and/or ß2-adrenoreceptor antagonist or agonist, followed by a cytokine production analysis using ELISA. Norepinephrine suppressed IL-17 and IFN-γ production by the anti-CD3/anti-CD28-microbead-stimulated CD4+ T cells in both groups. Blockade of the ß2-adrenoreceptor with the specific antagonist ICI 118.551 enhanced norepinephrine-mediated IL-17 suppression but decreased its inhibitory effect on IFN-γ production in MS patients. In contrast, the ß2-adrenoreceptor agonist formoterol did not influence norepinephrine's inhibitory effect on cytokine production in both groups. The blockade of the ß2-adrenoreceptor, even in the absence of exogenous norepinephrine, suppressed IL-17 production but did not influence IFN-γ production in both groups. Conversely, ß2-adrenoreceptor activation by formoterol decreased IFN-γ production and did not affect IL-17 production in both groups. These data illustrate the inhibitory effect of norepinephrine on IL-17 and IFN-γ production by CD4+ T cells in MS. The inhibitory effect of norepinephrine on IFN-γ production by CD4+ T cells in MS could be mediated via ß2-adrenoreceptor activation.

The Role of D2-like Dopaminergic Receptor in Dopamine-mediated Modulation of Th17-cells in Multiple Sclerosis.

BACKGROUND: Dopamine is one of the main mediators capable regulate the neuroimmune interaction and is involved in multiple sclerosis (MS) pathogenesis. OBJECTIVE: The aim of this study was to clarify the role of dopamine and its receptors in modulation of Th17-cells in MS. METHODS: 34 relapsing-remitting MS patients and 23 healthy subjects were examined. To assess the effect of dopamine on Th17-cells, CD4+ T-cells were cultured in the presence of dopamine and antagonist or agonist of D1- or D2-like dopaminergic receptors and stimulated with anti-CD3/CD28- microbeads. The levels of cytokines in supernatants were assessed by ELISA. RESULTS: Production of interleukin-17 (IL-17), interferon-γ (IFN-γ), granulocyte-colony stimulating factor (GM-CSF), and IL-21 by CD4+ T-cells as well as dopamine were comparable between the groups. Dopamine suppressed cytokine secretion by activated СD4+ T-cells in both groups. Blockade of D1-like dopaminergic receptor with a specific antagonist SCH23390 did not affect dopaminemediated cytokine suppression. In contrast, blockade of D2-like dopaminergic receptor by sulpiride decreased dopamine's inhibitory effect on IL-17 secretion in both groups and GM-CSF and IL-21 production in MS patients. Blockade of D1-like dopaminergic receptor directly inhibited IL-17, IFN- γ, GM-CSF in both groups and IL-21 production in healthy subjects, while blockade of D2-like dopaminergic receptor had no effect on cytokine secretion. Finally, activation of D2-like dopaminergic receptor with a specific agonist quinpirole decreased cytokine production in both groups. CONCLUSION: These data suggest an inhibitory role of dopamine on Th17-cells in MS, which could be mediated by the activation of the D2-like dopaminergic receptor.

The role of 5-HT2B-receptors in fluoxetine-mediated modulation of Th17- and Th1-cells in multiple sclerosis.

Fluoxetine is a selective serotonin reuptake inhibitor, which also has an immunomodulatory effect. We investigated the effects of fluoxetine and serotonin (5-HT) on the pro-inflammatory Th17- and Th1-cells in 30 patients with relapsing-remitting MS and 20 healthy subjects. Fluoxetine and 5-HT suppressed IL-17, IFN-γ and GM-CSF production by stimulated СD4+ T-cells in both groups. Blockade of 5-HT2B-receptors decreased the inhibitory effect of fluoxetine on cytokine production in MS patients. Finally, 5-HT2B-receptor activation inhibits IL-17, IFN-γ and GM-CSF production in both groups. These data suggest an anti-inflammatory role for fluoxetine in MS, which could be mediated by the activation of 5-HT2B-receptors.

Serotoninergic system targeting in multiple sclerosis: the prospective for pathogenetic therapy.

Serotonin (5-hydroxytryptamine) (5-HT) is a neurotransmitter, which mediates neuropsychological functions of the central nervous system (CNS). Recent studies have shown the modulatory effect of 5-HT on gut microbiota functions, which play an essential role in developing CNS inflammatory diseases. Finally, 5-HT is a direct mediator of neuroimmune interaction. The article reviews the literature data on the role of 5-HT in the regulation of neuroinflammation in multiple sclerosis (MS). The influence of 5-HT and selective serotonin reuptake inhibitors (SSRIs) on experimental autoimmune encephalomyelitis (EAE) and MS pathogenesis, as well as the therapeutic potential of serotoninergic drugs as a pathogenetic therapy of MS, are discussed.

The influence of glatiramer acetate on Th17-immune response in multiple sclerosis.

Glatiramer acetate (GA) is approved for the treatment of multiple sclerosis (MS). However, the mechanism of action of GA in MS is still unclear. In particular, it is not known whether GA can modulate the pro-inflammatory Th17-type immune response in MS. We investigated the effects of original GA (Copaxone®, Teva, Israel) and generic GA (Timexone®, Biocad, Russia) on Th17- and Th1-type cytokine production in vitro in 25 patients with relapsing-remitting MS and 25 healthy subjects. Both original and generic GA at concentrations 50-200 µg/ml dose-dependently inhibited interleukin-17 and interferon-γ production by anti-CD3/anti-CD28-activated peripheral blood mononuclear cells from MS patients and healthy subjects. This effect of GA was reproduced using purified CD4+ T cells, suggesting that GA can directly modulate the functions of Th17 and Th1 cells. At high concentrations (100-200 µg/ml), GA also suppressed the production of Th17-differentiation cytokines (interleukin-1ß and interleukin-6) by lipopolysaccharide (LPS)-activated dendritic cells (DCs). These GA/LPS-treated DCs induced lower interleukin-17 and interferon-γ production by autologous CD4+ T cells compared to LPS-treated DCs. These data suggest that GA can inhibit Th17-immune response and that this inhibitory effect is preferentially exercised by direct influence of GA on T cells. We also demonstrate a comparable ability of original and generic GA to modulate pro-inflammatory cytokine production.

Dopaminergic Therapeutics in Multiple Sclerosis: Focus on Th17-Cell Functions.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) with an autoimmune mechanism of development. Currently, one of the most promising directions in the study of MS pathogenesis are the neuroimmune interactions. Dopamine is one of the key neurotransmitters in CNS. Furthermore, dopamine is a direct mediator of interactions between the immune and nervous systems and can influence MS pathogenesis by modulating immune cells activity and cytokine production. Recent studies have shown that dopamine can enhance or inhibit the functions of innate and adaptive immune system, depending on the activation of different dopaminergic receptors, and can therefore influence the course of experimental autoimmune encephalomyelitis (EAE) and MS. In this review, we discuss putative dopaminergic therapeutics in EAE and MS with focus on Th17-cells, which are thought to play crucial role in MS pathogenesis. We suggest that targeting dopaminergic receptors could be explored as a new kind of disease-modifying treatment of MS. Graphical Abstract.

The Possibility of Preventive and Therapeutic Use of Green Tea Catechins in Prostate Cancer.

BACKGROUND: Prostate cancer is one of the most frequent types of cancer. Despite the existence of various treatment strategies, treatment of prostate cancer still presents serious difficulties (especially in advanced stages). Polyphenols have been extensively assessed in terms of their potential use for prostate cancer treatment and prevention. Catechins are among the most well-known polyphenols in this respect. OBJECTIVE: In this review, we summarize clinical study results concerning catechin applications with regard to prostate cancer treatment and prevention. We discuss some of the main mechanisms of the anticarcinogenic action of catechins. CONCLUSION: The main mechanisms of the anticarcinogenic action of catechins are subdivided into two major types: (i) direct action on cancer cells and (ii) indirect effect based on catechins's impact on the microenvironment of cancer cells, particularly in relation to the immune system. At this level catechins might reduce tumor-associated inflammation and immune tolerance.

The influence of biogenic amines on Th17-mediated immune response in multiple sclerosis.

Biogenic amines are direct mediators of interactions between immune and nervous systems implicated in the pathogenesis of multiple sclerosis (MS). Recently, great attention has been drawn to studying the effects of biogenic amines on Th17-cells, which play one of the central roles in the development of inflammatory lesions in MS. Results of these studies suggest that, depending on the activation of particular receptors, biogenic amines can both enhance and inhibit Th17-cell functions. Based on these data, targeting biogenic amines and their receptors could be explored as a new kind of additional disease-modifying treatment of MS.

The Linkage Between Inflammation and Immune Tolerance: Interfering with Inflammation in Cancer.

BACKGROUND: It is widely accepted that chronic inflammation critically contributes to cancer. Immune tolerance in cancer mediates tumor escape from the immune system. The mechanisms of relations between inflammation and immune tolerance are still not fully elucidated. OBJECTIVE: The main mechanisms that link inflammation and tolerance are considered. Drug targets that are in use to interfere with inflammation in cancer are discussed. CONCLUSION: Inflammation mediates tumor-induced tolerance. The induction and the maintenance of the chronic inflammatory response is a universal mechanism of immune tolerance.