Madhappan B

Flavonols inhibit proinflammatory mediator release, intracellular calcium ion levels and protein kinase C theta phosphorylation in human mast cells

1 Mast cells participate in allergies, and also in immunity and inflammation by secreting proinflammatory cytokines. 2 Flavonoids are naturally occurring polyphenolic plant compounds, one group of which – the flavonols, inhibits histamine and some cytokine release from rodent basophils and mast cells. However, the effect of flavonols on proinflammatory mediator release and their possible mechanism of action in human mast cells is not well defined. 3 Human umbilical cord blood‐derived cultured mast cells (hCBMCs) grown in the presence of stem cell factor (SCF) and interleukin (IL)‐6 were preincubated for 15 min with the flavonols quercetin, kaempferol, myricetin and morin (0.01, 0.1, 1, 10 or 100 μM), followed by activation with anti‐IgE. Secretion was quantitated for IL‐6, IL‐8, tumor necrosis factor‐alpha (TNF‐α), histamine and tryptase levels. 4 Release of IL‐6, IL‐8 and TNF‐α was inhibited by 82–93% at 100 μM quercetin and kaempferol, and 31–70% by myricetin and morin. Tryptase release was inhibited by 79–96% at 100 μM quercetin, kampferol and myricetin, but only 39% by morin; histamine release was inhibited 52–77% by the first three flavonols, but only 28% by morin. These flavonols suppressed intracellular calcium ion elevations in a dose–response manner, with morin being the weakest; they also inhibited phosphorylation of the calcium‐insensitive protein kinase C theta (PKC θ). 5 Flavonol inhibition of IgE‐mediated proinflammatory mediator release from hCBMCs may be due to inhibition of intracellular calcium influx and PKC θ signaling. Flavonols may therefore be suitable for the treatment of allergic and inflammatory diseases.

IL-10 subfamily members: IL-19, IL-20, IL-22, IL-24 and IL-26

It has been reported that the CD4+ T cell is a very important source of interleukin 10 (IL-10), while CD8+ cells produce low amounts. IL-10 exerts several immune stimulating, as well as inhibitory effects. There are at least five novel human IL-10 family-related molecules: IL-19, IL-20, IL-22, IL-24, and IL-26. Activated T cells produce IL-19, IL-22 and IL-26, while IL-24 is produced by activated monocytes and T-cells. IL-20 induces cheratin proliferation and Stat-3 signal transduction pathway, while IL-22 induces acute-phase production by hepatocytes and neonatal lethality with skin abnormalities reminiscent of psoriasic lesions in humans. In addition, IL-22 mediates inflammation and binds class II cytokine receptor heterodimers IL-22 RA1/CRF2-4. This cytokine is also involved in immuno-regulatory responses. IL-26 (AK155) is a novel cytokine generated by memory cells and is involved in the transformed phenotype of human T cells after infection by herpes virus. All these new IL-10 subfamily member cytokines are strongly involved in immune regulation and inflammatory responses.

Increased numbers of activated mast cells in endometriosis lesions positive for corticotropin-releasing hormone and urocortin.

Problem:  Mast cells are critical in allergic and inflammatory diseases such as interstitial cystitis, which is often clinically associated with or mistaken as endometriosis. Mast cells had previously been reported to be increased at sites of endometriosis, and tryptase may contribute to the fibrosis and inflammation characterizing endometriosis.

T lymphocyte subsets and immunoglobulins in intracranial tumor patients before and after treatment, and based on histological type of tumors.

It has been reported that nervous system and peripheral immune system communicate with each other and the peripheral immune status is depressed in some intracranial tumor (ICT) patients pre operatively. Little is known about the immune status of intracranial tumor patients during the post operative survival period. We thus investigated total T cells (CD 11+), helper/inducer (CD4+) T cells, suppressor/cytotoxic (CD8+) T cells, B cells (CD19+) and serum immunoglobulins in peripheral blood in certain ICT patients before and after treatment, and based on the histological type of the tumors. Post treatment analysis were conducted 30 days after surgical removal of tumor tissue in benign brain tumor patients and 30 days after chemo therapy (CT)/radiotherapy (RT) following surgical removal of tumor tissue in malignant brain tumor patients. Decreased CD11+, CD4+ and increased CD8+ T cell counts were observed in both benign and malignant tumor cases before treatment compared with control subjects. After treatment, CD4+ T cell count increased and CD8+ T cell count decreased than their pre treatment levels. Serum IgA and IgG levels were decreased in both benign and malignant brain tumor patients before treatment than in control subjects. Serum IgM level has been increased in both benign and malignant tumor patients before and after treatment than in control subjects. Anaplastic malignant astrocytoma, medulloblastoma and glioblastoma multiforme patients showed higher IgM level than astrocytoma, meningioma and ependymoma patients. In conclusions, the depressed host cellular immunity in benign and malignant tumor patients before treatment may be due to the changes in CD4+ and CD8+ counts in addition to tumour specific immunosuppressive factors. Treatment procedures such as surgery, CT and RT may play certain role in the post operative depressed immunosuppression in malignant tumor patients. Humoral immune mechanism (CD19+) in the ICT patients was less markedly affected.

The proinflammatory interleukin-21 elicits anti-tumor response and mediates autoimmunity.

Interleukins (IL) are inflammatory proteins (except IL-4 and IL-10) that modulate the immune system (1-4). IL-2l induced inflammation in vivo, based on recruitment of neutrophil and monocyte populations (5-8). This cytokine is similar in primary sequence and structure to IL-2 and IL-15 and is a member of the type I cytokine superfamily which includes IL-2, IL-4, IL-7, IL-9, IL-ll, IL-12, IL-13, IL-15 and Colony Stimulating Factors (CSFs). IL-2l is a multifunctional cytokine having roles in both innate and adaptive immune responses of the Th 1 type (9-11) with an effect on proliferation, apoptosis and differentiation of T cells, NK cells, dendritic cells and B cells (12-15) and lymphocytes function (16-18) (Fig. 1). IL-21, like other members of this family, is a gamma-chain dependent cytokine playing a prominent role in promoting and maintaining T cell populations (19-21). Human and murine IL-2l are 57% identical at the amino acid level, display a 4helix-bundle-type with homology to IL-2, IL-4 and IL-15 and have a unique receptor, IL-21R. The exon and intron structure of the IL-2 and IL-2l genes are very similar and are related to each other. IL21R is a type I cytokine receptor that acts through the interaction with the common gamma chain and is expressed in lymphoid tissues: thymus, spleen, peripheral blood leukocytes such as T cells (CD4+ and CD8+), B cells, NK cells, dendritic cells and several cell lines (22-24). IL-2l R possesses alpha, beta and gamma chain heterotrimer. The beta and gamma chain are essential for signal transduction while the alpha subunit seems to be more involved in high-affinity binding conversion. An anti-gamma chain antibody inhibits cell proliferation induced by IL-2l, suggesting that the gamma chain plays an essential role in IL-2l signal transduction (2527). The generation of IL-21R-deficient mice with normal lymphoid cells revealed dysfunction in immunoglobulin IgG1 production and an increase in IgE responses in immunized animals (28-30). IL-2l needs the common gamma chain to mediate the intracellular survival and/or mitogenic signalling, which occurs through the essential transducermolecule JAK3 (5, 31); however, three major pathways are involved in IL-2l signalling ( JAKISTAT, MAPK and PI3K) to promote and maintain T lymphocyte populations (32-34). Survival and differentiation of B cells is mediated by IL-2l through down-regulation of anti-apoptotic proteins and up-regulation of proapoptotic proteins (35-38).

Interleukin-25 (or IL-17E): a new IL-17 family member with growth factor/inflammatory actions.

Interleukins are cytokines that control the development and differentiation lineage of blood cells from pluripotent stem cells; many of them are also potent inflammatory proteins (1-29). InterleukinI 7 aT-lymphocyte related cytokine is a homodimeric protein of about 32 kDa reportedly secreted by CD4+ activated memory (CD45+RO+) T cells and is a major vehicle by which T cells communicate with the hematopoietic system (18). Interleukin-25 (IL-25) or ILI 7E, is a new member of the ILI 7 cytokine family, along with IL-17F. Tulin E.E. et al. described the new protein termed SF20/IL-25, isolated after secretion by bone marrow stroma-derived growth factor (20). When this protein binds its receptor, the cells proliferate (30). These authors reported that SF20/ IL-25 induces the proliferation of lymphoid, but not myeloid cells (20). Independently, Fort M.M. et aI. reported that a new cytokine termed IL-25 was characterized from Th2 cells (31). IL-25 was reported to induce IL-4, IL-5 and IL-13 gene expression when injected in mice (31). In addition, IL-25 was capable of activating Th2 cells and increasing serum levels of IgG I, IgE and IgA; IL25 also increased the number of eosinophils in the blood, and provoked pathological effects in the lung and digestive tract correlated to the increases of eosinophil infiltration (3 I). These findings suggest that IL-25 is involved in allergic inflammation and the activity of Th2 cells (31). In 2002, Hurst SD et al. reported about the two new members of the IL17 cytokine family: IL-17F and IL-25 (32). These authors confirmed a previous finding that IL-25 provokes the production of IL-4, IL-5 and IL13. In addition, they found that this new member of the IL-17 is capable of stimulating the chemokine eotaxin at the mRNA level in the lung (32), which is a very important inflammatory mediator. Moreover, intranasal administration of IL-25 caused epithelial cell hyperplasia, increased mucus secretion and airway hyperreactivity (32). These results confirmed that IL-25 plays an important role in inflammation, especially in allergic reactions. The latest report on IL-25 was published by Ikeda K et al. (33). These authors also confirmed that IL-25 is an IL17 family member and a Th2 cell derived cytokine capable of inducing the production of IL-4, IL-5 and IL13from an unidentified non-TceII population (33). These authors reported that bone marrowderived mast cells can also generate large amount of IL-25 protein and IL-25 mRNA when the cells

Some aspects of Parasitology and Immunology in general Medicine.

The objective of these studies is to review the role of some parasites and their components in inflammation, allergy and immune system. We also report recent results published by others group as well as our own.

Role of flavonoids and vitamins in cancer.

Flavonoids are naturally occurring polyphenolic plant compounds that are capable of inhibiting histamine and cytokine release from several cells. Many studies suggest that flavonoids are anticancer agents with an apoptotic effect on tumor cells. Studies with animal tumour models have found vitamin deficiency to enhance susceptibility to chemical carcinogenesis and large doses of anti-oxidant vitamins and flavonoids to inhibit carcinogenesis. In some studies flavonoids and/or vitamins were found to reduce the predisposition to develop tumours in animals and humans. In conclusion, in this review we describe the role of flavonoids and vitamins in cancer.