The plasmatic and salivary levels of IL-1ß, IL-18 and IL-6 are associated to emotional difference during stress in young male.

Saliva collection is considered a non-invasive method to detect inflammatory markers in response to emotional states within natural social contexts. Numerous studies have prompted an important role of cytokines in modulating distinct aspects of social and emotional behavior. The aim of this study was to investigate the reliability of plasma and saliva as investigative tools for measure some inflammatory marker levels (CRP, IL-1ß, IL-18, and IL-6). At the same time, the relationships between these markers and emotional states in response to a socio-cognitive stress (Academic Exam, AE), were considered. It was demonstrated that the plasma and saliva concentrations of all immune-mediators analyzed were significantly related across the socio-cognitive stress. In addition, when there was a close correlation to AE, the anger state, the IL-1ß, the IL-18 salivary and plasmatic concentrations were significantly higher, while they decreased during the AE. On the other hand, the anxiety state and the IL-6 levels significantly increased throughout the AE. The IL-1ß and IL-6 were positively associated to the anger and the anxiety state, respectively. In conclusion, our data highlight that different immune markers are similarly detectable in plasma and saliva during socio-cognitive stress. Also, they could be related to different emotional responses.

Super-oxide anion production and antioxidant enzymatic activities associated with the executive functions in peripheral blood mononuclear cells of healthy adult samples.

Executive Functions (EFs) involve a set of high cognitive abilities impairment which have been successfully related to a redox omeostasis imbalance in several psychiatric disorders. Firstly, we aimed to investigate the relationship between executive functioning and some oxidative metabolism parameters in Peripheral Blood Mononuclear Cells (PBMCs) from healthy adult samples. The Brown Attention-Deficit Disorder Scales were administered to assess five specific facets of executive functioning. Total superoxide anion production, Super Oxide Dismutase (SOD), Catalase (CAT), Glutathione Reductase (GR) and Glutathione Peroxidase (GPx) activities were evaluated on proteins extracted from the PBMCs. We found significant positive correlations between superoxide anion production and the total score of the 'Brown' Scale and some of its clusters. The GPx and CAT activities were negatively associated with the total score and some clusters. In a linear regression analysis, these biological variables were indicated as the most salient predictors of the total score, explaining the 24% variance (adjusted R(2)=0.24, ANOVA, p<.001). This study provides novel evidence that Executive Functions have underpinnings in the oxidative metabolism, as ascertained in healthy subjects.

Negative feedback interaction of HO-1/INOS in PBMC of acute congestive heart failure patients.

Heart failure (HF) is a common clinical syndrome with frequent exacerbations requiring hospitalization. Among the various mechanisms that underlie the pathogenesis of HF, the activation of the immune system leads to a progressive and redundant release of proinflammatory cytokines responsible for a variety of deleterious effects in heart failure, such as endothelial dysfunction, apoptosis of myocytes, activation of MMPs (Matrix Metallo Proteinases) and oxidative stress, with the result of decreased inotropism and clinical syndrome such as pulmonary edema,. The condition of oxidative stress induces the expression of genes coding for the proteins inducible nitric oxide synthase (iNOS) and heme oxygenase-1 (HO-1). Twenty-five hospitalized cardiology patients with symptomatic acute congestive HF (NYHA Class III-IV) and impaired left ventricular (LV) function (ejection fraction less than 35 percent) were included in the study. The aim of this study was to evaluate the cytokines plasma concentrations and the expression and activity of iNOS and HO-1 proteins in peripheral blood mononuclear cell (PBMC) extracted from patients in comparison to control group. In ACHF; left ventricular ejection fraction (LVEF) percent was reduced. Furthermore; iNOS and HO-1 expression and cytokines plasma levels were significantly higher in patients with ACHF as compared to controls group. Moreover the enzyme activity presents an opposite trend compared to that obtained in the analysis of the transcript and proteins. Our studies suggest a negative feedback interaction between iNOS and HO-1 important in the physiopathology of heart failure that could be considered a good candidate as a future therapeutic target for the development of new drugs.

Biological role of interleukin-1beta in defensive-aggressive behaviour.

During the past decade, a great deal of data has accumulated supporting the notion that cytokines interact to regulate several aspects of social and emotional behaviour. There are reports of a positive correlation between cytokine levels and aggressive behaviour in healthy populations, and clinical reports describe an increase of aggressive traits in patients who receive cytokine immunotherapy. Interleukin-1beta released during an immune response acts as messenger that helps to modulate behaviour by influencing relevant neurotransmitter systems, and in some cases, by directly acting within the brain. In this site, IL-1beta exerts its actions by acting through 5-HT2 and IL-1 Type I receptors in hypothalamus or by potentially indirect routes, including activation of sensory afferents, and stimulation of cytokine release by brain endothelial cells. This review reports research investigating the relationship between IL-1beta, and the immune and central nervous systems involving or potentially involving defensive aggressive behaviour.

Allergic inflammation: role of cytokines with special emphasis on IL-4.

This review examines recent articles on the relationship of cytokines to allergy and inflammation with particular emphasis on interleukin (IL)-4. The objective of this article is therefore to review published studies to identify cytokines consistently involved in allergic inflammation. Proinflammatory cytokines, including IL-4, IL-5, IL-13 and GM-CSF along with TNF-alpha play a role in allergen-induced airway leukocyte recruitment and these cytokines can be generated by T mast cells and other cells. In addition, IL-9, IL-25, IL-33, IL-17, IL-27 and IFN-gamma are deeply involved in the regulation of asthma. Blocking the effect of these proinflammatory cytokines might provide new therapeutic approaches for the control of allergy and inflammation.

Impact of IL-18 on inflammation.

IL-18 is produced by many cell types, such as Kupffer cells, keratinocytes, macrophages, dendritic cells, and activated T cells stimulated by LPS. It is an important regulator of both innate and acquired immune responses. IL-18 plays a central role in rheumatoid arthritis since the T cells and macrophages that invade the synovial. These finding support a role for IL-18 in inflammation, allergy and immune diseases.

Interrelationship between vitamins and cytokines in immunity.

Cytokines are important proteins that modulate immunity and inflammation. Vitamins are also involved in immunity and inflammation. They are found to restore the ability of some cells to produce certain cytokines. Vitamin deficiency appears to affect the mechanism of immune cells, though the impact of reduced cytokine response in vitamin malnutrition is not clear. Vitamin D is involved in many medical conditions, such as infections and inflammation, and mediates innate immunity. Deficiency of vitamin D increases the risk of infectious and inflammatory diseases. In addition, this vitamin modulates Treg function and IL-10 production which is important for therapeutic treatment. Vitamin A increases inflammatory response and is involved in tissue damage; moreover, vitamin A is a key modulator of TGFbeta which can suppress several cytokines. Vitamin E, an anti-ageing compound, is associated with a defect of naive T cells and may inhibit some inflammatory compounds such as prostaglandin generation.

IL-31 a Th2 cytokine involved in immunity and inflammation.

Cytokines are immunal regulatory proteins, however they also play a relevant role in inflammatory diseases. IL-31 is a newly discovered cytokine expressed primarily in TH2 cells, introduced by activated CD4+ T cells. IL-31 is capable of inducing chemokines and other cytokines in several inflammatory diseases via its surface receptor. This cytokine is also produced by mast cells and mast cell line, suggesting a role in allergic diseases. In this editorial we revisit the biological role of IL-31 in immunity and inflammation.

VEGF, substance P and stress, new aspects: a revisited study.

Mast cells play an essential role in diverse physiological and pathological processes, such as atherosclerosis, malignancy, asthma, pulmonary fibrosis and arthritis, directly interact with bacteria, and appear to play a vital role in host defense against pathogens. Mast cells could be recruited in the inflammatory site, by MCP-1, RANTES and SCF, to selectively secrete proinflammatory molecules; these could include growth factors, histamine, which is mitogenic (H1) and an immunosuppressant (H2), neovascularization agents, such as heparin, IL-8, and VEGF, as well as proteases that could permit new blood vessel formation. Neurogenic inflammation involves vasodilation and plasma protein extravasation in response to neural stimulation. Upon stimulation, sensory neurons release Substance P and other neuropeptides and activate neurokinin-1 receptors leading to plasma protein extravasation from post-capillary venules. Substance P is a neuropeptide that is released from nerve endings in many tissues and plays an important role in immunological and inflammatory states, and it is also a mediator of tissue injury, asthma, arthritis, allergy and autoimmune diseases. SP-positive nerve fibers and mast cell contacts are increased by acute stress in mice leading to dermal mast cell degranulation. VEGF is produced by flammatory cells. IL-33 is the newest inflammatory member of the IL-1 cytokine family and we show here that SP can induce VEGF secretion from mast cells and IL-33 augments the effect of SP in VEGF transcription and translation protein.

IL-35, an anti-inflammatory cytokine which expands CD4+CD25+ Treg Cells.

Interleukin 12 (IL 12) p35/p40 is a heterodimeric cytokine which plays a critical role in inflammation, immunity and tissue proliferation, and also plays a relevant function in T helper (Th) cell polarization and Th1 T-cell differentiation. IL-12 family members, IL-12p70, IL-23, IL-27 and IL-35, play an important role in influencing helper T-cell differentiation. EBV-induced gene 3 can be associated with the p35 subunit of IL-12 to form the EBI3/p35 heterodimer, also called IL-35. It has been shown that IL-35 has biological activity and able to expand CD4+CD25+ Treg cells, suppress the proliferation of CD4+CD25- effector cells and inhibit Th17 cell polarization. IL-35 has been shown to be constitutively expressed by regulatory T (Treg) cells CD4(+)CD25(+)Foxp3(+) and suggested to contribute to their suppressive activity. IL-35 is a crucial mediator which provokes CD4+CD25+ T cell proliferation and IL-10 generation, another well-known anti-inflammatory cytokine, along with TGFbeta cytokine. These studies suggest that IL-35, together with other successfully discovered cytokine inhibitors, represents a new potential therapeutic cytokine for chronic inflammation, autoimmunity and other immunological disorders.

Impact of RANTES, MCP-1 and IL-8 in mast cells.

Chemokines are cytokines with chemotactic properties on inflammatory cells and other cell types. RANTES, MCP-1 and related molecules, constitute the C-C class of chemokine supergene family and a group of cytokines produced by hematopoietic cells, while IL-8 constitute the C-X-C class. The roles of most of these chemokines are not well known, although members of the chemokine family are inflammatory agents. The C-C chemokine plays a role in regulating Th-cell cytokine production and leukocyte trafficking. In this study we clearly show that RANTES and MCP-1 are mediators of acute inflammatory responses. Our report describes additional biological activities for RANTES, MCP-1, and IL-8, suggesting that these chemokines play a fundamental role in histamine and serotonin generation and cell function in mast cells.

Vitamins and mast cells.

The immune system is a highly complex, intricately regulated group of cells whose integrated function is essential to health. The mast cell inflammatory response is characterized by an early phase with massive discharge of mediators stored in cytoplasmic secretory granules. Through multigranular/compound exocytosis and a late phase that involves generation of arachidonic acid metabolites and de novo synthesis of cytokines/chemokines and growth factors. Vitamins have been shown to have a protective effect on the body's immune cells. Vitamin C and E are necessary in allergic disease treatment where mast cells are involved. In addition, ascorbic acid and pyridoxine are useful compounds for the treatment of inflammatory disorder of the respiratory airways. Here we revisited the inter-relationship between vitamins and mast cells.

Infections and mast cells.

Mast cells play a role in various physiological functions: innate and acquired immunity, epithelium remodelling and proliferation, angiogenesis, cancer, inflammation and infections. Mast cells are activated by cross-linking of FcERI molecules, which are involved in the binding of multivalent antigens to the attached IgE molecules, resulting in a variety of responses including the immediate release of potent inflammatory mediators. In addition, mast cell biology consists in the capability to secrete preformed mediators which include biogenic amines and newly synthetized mediators, which include lipid-derived mediators and cytokines. It has been reported that parasite infections induce a systemic immunomodulatory network, including regulatory T cells, pro-inflammatory and anti-inflammatory cytokines, which might play a key role in the allergic phenotype. Here, in this article, we revisited the relationship between mast cells and infections.

IL-32: a newly-discovered proinflammatory cytokine.

IL-32, a newly-discovered proinflammatory cytokine that activates the p38MAPK and NF-kappaB pathways, is an important player in innate and adaptive immune response. IL-32, a cytokine produced mainly by T, natural killer, and epithelial cells induces significant amounts of TNFalpha and MIP-2 and increases the production of both cytokines in a dose-dependent manner. IL-32 has been implicated in inflammatory disorders, mycobacterium tuberculosis infections, inflammatory bowel disease, and influenza A virus infection, as well as in some autoimmune diseases, such as rheumatoid arthritis, ulcerative colitis and Crohn?s disease and in human stomach cancer, human lung cancer and breast cancer tissues. Moreover, it has been reported that IL-32 has pro-inflammatory effects on myeloid cells and causes the differentiation of osteoclast precursors into multinucleated cells expressing specific osteoclast markers. We recently found that human IL-32 has the capacity to provoke histamine release in human-derived cord blood mast cells (HDCBMC), but not in LAD 2 cells nor in rat peritoneal mast cells (RPMC), showing that IL-32 may be specie specific and act more in mature human mast cells (HDCBMC) than in transformed mast cells (LAD 2 cells). Certainly, IL-32 is another potent proinflammatory cytokine, however, the specific role of this newly-discovered protein in the network of cytokine biology remains to be determined.

Anti-inflammatory properties of the plant Verbascum mallophorum.

Verbascum mallophorum is part of a large family of Scrophulariaceae consisting of more than 360 species. Verbascum mallophorums contains diverse polysaccharides, iroid glycosides, flavonoids, saponins, volatile oils and phenylentanoids. Verbascum has been used in popular medicine for treating wounds, chilblains, respiratory ailments, acne and arthritic disturbances. Inducible nitric oxide synthase (iNOS) represents one of the three isoforms that produce nitric oxide using L-arginine as a substrate in response to an increase in superoxide anion activated by NF-kappaB. It is implicated in different pathophysiological events and its expression increases greatly during an inflammatory process due to oxidative stress. In our study we reproduced an inflammatory state by treating THP-1 cells (human myelomonocytic leukaemia) with pro-inflammatory stimuli, such as LPS and IFN-gamma, obtaining an up-regulation both in the expression and in the activity of iNOS. The aim of our work is to investigate the possible antiinflammatory action of verbascoside extract from Verbascum mallophorum using a concentration of 100 muM. Our results show a significant decrease in the expression and activity of iNOS and extracellular O2- when cells were treated with verbascoside. Based on these results we hypothesize that verbascoside extract from Verbascum mallophorum has anti-inflammatory properties since it reduces the production of superoxide radicals and consequently reduces the activity of iNOS.

RANTES (CCL5) potentiates calcium ionophore in the production of LTB4 in rat adherent macrophages from granuloma induced by KMnO4: inhibiton by NDGA.

The activation of monocytes/macrophages by several stimuli is an initial event in the inflammatory response. To ascertain the importance of LTB(4) and 5-lypoxigenase in the inflammatory site, we isolated and stimulated rat adherent granuloma macrophages (RAGMs) with calcium ionophore in the presence or absence of regulated on activation, normal T expressed and secreted (RANTES) [CCL5] at different concentrations. We tested the hypothesis that RANTES may influence the production of LTB(4) stimulated by calcium ionophore A23187 (2.5 microM/ml) in rat adherent granuloma macrophages derived from granuloma induced by potassium permanganate diluted 1:40 saturated solution. To test this hypothesis, we measured LTB(4) production, in rat granuloma macrophages stimulated with A23187 (2.5 microM) alone and in combination with RANTES at different concentrations. In these studies, the cell-free supernatant of stimulated RAGMs with the ionophore A23187, resulted in a drastic increase of LTB(4). However, when the cells were treated with the combination RANTES plus A23187 the stimulatory effect was more pronounced than A23187 alone. LTB(4) production was quantitated. The calcium ionophore A23187 directly induced LTB(4) in macrophages, this production was markedly enhanced when the cells were pretreated with RANTES. However, the addition of RANTES in the absence of calcium ionophore A23187 did not directly induce LTB(4) release, nor was lypoxigenase expression augmented. Preincubation of RAGMs with NDGA (nordihydroguiaretic acid) (10(-5)M) completely abolished the production of LTB4 on RAGMSs challenged with A23187 in combination with RANTES or A23187 alone in the supernatants. Similar effects were obtained when the cells were pretreated with dexamethasone. These data suggest, for the first time, that RANTES may stimulate the release of LTB(4), only when it is associated to other stimuli and for this reason we conclude that RANTES modulates inflammatory diseases, and may require other stimuli to be effective in amplifying its spectrum of action(s).

Phosphodiesterase type-5 inhibitor and oxidative stress.

Erectile dysfunction (ED) is a common medical condition that affects the sexual life of millions of men worldwide. Numerous physical and psychological factors are involved in normal erectile function, including neurological, vascular, hormonal and cavernous functions. The current therapy for the condition is pharmacological and psychotherapeutic which regulates the erectile function and amplifies the NO-mediated response. The aim of this work is to test the action of three common phosphodiesterase inhibitors: Tadalafil, Sildenafil Citrate and Vardenafil at 0.05 microM on human monocytes, analyzing the expression of iNOS protein and mRNA by Western blot and rt-PCR, and production of NO by conversion of L-(2,3,4,5)-[3H]Arginine to L-(3H) citrulline. We also tested the efficiency of the antioxidant network by spectrophotometer (SOD, CAT, GPx and Gr), under normal conditions and after stimulation with LPS. The results showed an increase in ROS levels, similar for all the molecules with regard to the antioxidant enzymes. In all cases the treatment determines a response to the limited efficiency, arriving at a situation in which phosphodiesterase inhibitors + LPS clearly show oxidative stress.

Localization and activity of iNOS in normal human lung tissue and lung cancer tissue.

Inducible nitric oxide synthase (iNOS) is one of three enzymes generating nitric oxide (NO) from the amino acid L-arginine. iNOS-derived NO plays an important role in several physiological and pathophysiological conditions. NO is a free radical which produces many reactive intermediates that account for its bioactivity. In the human lung, the alveolar macrophage is an important producer of cytokines and this production may be modified by NO. Moreover, high concentrations of NO have been shown to increase nuclear factor kappaB (NF-kB) activation. Recent investigations of NO expression in tumor tissue indicated that, at least for certain tumors, NO may mediate one or more roles during the growth of human cancer. We have studied iNOS in two tissue groups: normal human lung tissue and human lung cancer tissue. We localized iNOS in these tissues by immunohistochemistry and tested the mRNA expression by RT-PCR, the protein level by Western blot, and the protein activity by radiometric analysis. The results demonstrate different expression, localization and activity of iNOS in normal versus tumor tissue. This is suggestive of a role for NO production from iNOS in human lung cancer because high concentrations of this short molecule may transform to highly reactive compounds such as peroxynitrite (ONOO-); moreover, through the upregulator NF-kB, they can induce a chronic inflammatory state representing an elevated risk for cell transformation to cancer.

TT virus infection: role of interferons, interleukin-28 and 29, cytokines and antiviral proteins.

In 1997 a novel virus in the serum of a patient with acute post-transfusion hepatitis of non A-G etiology was identified. This agent was designed TT virus (TTV). It produces persistent viremia and no disease, but the mechanism of its persistence is poorly understood. In the present study mRNA expression of antiviral proteins as MxA, 2' 5' OAS, anti-apopotic protein, cytokines IL- 28, IL- 29 and IFN are examined in a subject affected by B lymphoma and positive for TTV DNA and RNA in this cellular subset, and in BJAB and Dohh2 cell lines.