M.L. Castellani

Anti-chemokine therapy for inflammatory diseases.

Chemokines are inflammatory proteins acting via G-protein coupled chemokine receptors that trigger different signaling pathways. Monocyte chemoattractant protein-1 (CCL2/MCP-1) and regulated on activation, normal T expressed and secreted (CCL5/RANTES) are the two major members of the CC chemokine beta subfamily. The roles of RANTES and MCP-1 are emerging in regulating the recruitment of inflammatory cells into tissue during inflammation. The inhibition of MCP-1 and RANTES with corresponding antibodies or other inhibitors may provide benefits in different clinical scenarios including cancer, inflammation, CNS disorders, parasitic disease, autoimmune and heart diseases. RANTES and MCP-1 may represent targets for diagnostic procedures and therapeutic intervention, and may be useful as a prognostic factor in the above diseases.

Cytokines and the brain.

The specificity of an immune response is due to lymphocytes, the only cells in the body capable of specifically recognizing different antigenic determinants (1-10). Cytokines are modulatory proteins that control the development and differentiation of lymphocytes from pluripotent stem cells; many cytokines are also potent inflammatory molecules (11-15). Cytokines are secreted under stress (16), and it has been shown that acute stress induces leukocyte trafficking and augments immune responses (16-17).

Inhibitory effect of quercetin on tryptase and interleukin-6 release, and histidine decarboxylase mRNA transcription by human mast cell-1 cell line.

Mast cells are involved in inflammatory processes and in allergic reactions where immunologic stimulation leads to degranulation and generation of numerous cytokines and inflammatory mediators. Mast cells have been proposed as an immune gate to the brain, as well as sensors of environmental and emotional stress, and are likely involved in neuropathologic processes such as multiple sclerosis. Among mast cell products, the protease tryptase could be associated with neurodegenerative processes through the activation of specific receptors (PARs) expressed in the brain, while interleukin (IL)-6 likely causes neurodegeneration and exacerbates dysfunction induced by other cytokines; or it could have a protective effect against demyelinisation. In this report we show that quercetin, a natural compound able to act as an inhibitor of mast cell secretion, causes a decrease in the release of tryptase and IL-6 and the down-regulation of histidine decarboxylase (HDC) mRNA from human mast cell (HMC)-1 cells. As quercetin dramatically inhibits mast cell tryptase and IL-6 release and HDC mRNA transcription by HMC-1 cell line, these results nominate quercetin as a therapeutical compound in association with other therapeutical molecules for neurological diseases mediated by mast cell degranulation.

IL-37 (IL-1F7) the newest anti-inflammatory cytokine which suppresses immune responses and inflammation.

Cytokines such as interleukins, chemokines and interferons are immunomodulating and inflammatory agents, characterized by considerable redundancy, in that many cytokines appear to share similar functions. Virtually all nucleated cells, but especially epithelial cells and macrophages, are potent producers of cytokines. The objective of this study is to review the detailed mechanism of action and the biological profiles of IL-37, the newest anti-inflammatory cytokine. This review focuses on IL-37, a key cytokine in regulating inflammatory responses, mainly by inhibiting the expression, production and function of proinflammatory cytokines: IL-1 family pro-inflammatory effects are markedly suppressed by IL-37.

Autism and immunity: revisited study.

Autism spectrum disorder is of interest neurochemically because it represents a relatively homogeneous disorder with regard to disease development, abnormal cognitive development and intellectual development disturbance. A consistent finding in autistic children is a high number of mast cells and a high level of serotonin which is also found at elevated concentrations in the urine of autistic patients. In addition, a dysfunction of clinical conditions, such as gastrointestinal and immunological symptoms, is frequently noted in autistic children, however, IgE does not appear to be prevalent in these children but probably an increase of cytokines/chemokines produced by mast cells at an early age may play an important role. Therefore an immune hypothesis, involving also autoimmunity, is one possible pathogenetic mechanism in autism. In conclusion, mast cell activation could contribute to immune and neuroinflammatory abnormalities that are evident in patients with autism spectrum disorders.

Biology of neurotensin: revisited study.

The tridecapeptide neurotensin (NT) acts in the mammalian brain as a primary neurotransmitter or neuromodulator of classical neurotransmitters. Morphological and functional in vitro and in vivo studies have demonstrated the existence of close interactions between NT and dopamine both in limbic and in striatal brain regions. Additionally, biochemical and neurochemical evidence indicates that in these brain regions NT also plays a crucial role in the regulation of the aminoacidergic signalling. Immune cells, such as lymphocytes, macrophages and mast cells are reported to be activated by neuropeptides, such as neurotensin; this activation leads to cytokine and immunoglobulin production. In addition, neurotensin increases calcium level and the production of nitric oxide, therefore neurotensin is deeply involved in immunity and inflammation but its real function still remains to be elucidated.

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).

Impact of neuropeptide substance P an inflammatory compound on arachidonic acid compound generation

There is much evidence that neuropeptide substance P is involved in neurogenic inflammation and is an important neurotransmitter and neurmodulator compound. In addition, substance P plays an important role in inflammation and immunity. Macrophages can be activated by substance P which provokes the release of inflammatory compounds such as interleukins, chemokines and growth factors. Substance P is involved in the mechanism of pain through the trigeminal nerve which runs through the head, temporal and sinus cavity. Substance P also activates mast cells to release inflammatory mediators such as arachindonic acid compound, cytokines/chemokines and histamine. The release of these chemical mediators is crucial for inflammatory response. Among these mediators there are prostoglandins and leukotrines. Here we review the impact of substance P on inflammatory compounds.

Relevance of plant lectins in human cell biology and immunology.

Protein-carbohydrate interactions are used for intercellular communication. Mammalian cells are known to bear a variety of glycoconjugates. Lectins, first discovered in plants, are proteins which can specifically bind carbohydrates. Given the high affinity of plant lectins for carbohydrates, they have always been important as molecular tools in the identification, purification and stimulation of specific glycoproteins on human cells. Lectins have provided important clues to the repertoire of carbohydrate structures in animal cells. The discovery of plant lectins gave a great impulse to modern glycobiology. They represent important biochemical reagents for numerous applications in the biomedical field and in research. Sequence determinations and structural characterization helped to understand the mechanism of action in many biologic systems. Plant lectins have been fundamental in human immunological studies because some of them are mitogenic/activating to lymphocytes. Understanding the molecular basis of lectin-carbohydrate interactions and of the intracellular signalling evoked holds promise for the design of novel drugs for the treatment of infectious, inflammatory and malignant diseases. It may also be of help for the structural and functional investigation of glycoconjugates and their changes during physiological and pathological processes.

Inhibition of MCP-1 and MIP-2 chemokines in murine trichinellosis: effect of the anti-inflammatory compound L-mimosine.

Mimosine, is a plant amino-acid which has been reported to block DNA replication in mammalian cells and to arrest cells reversibly towards the end of the G1 phase or at the beginning of the S phase. In this study, 42 mice were infected with T. spiralis, a nematode parasite, and treated with the anti-inflammatory compound L-mimosine, to determine if any alteration in the chronic inflammatory state occurred, by investigating the hosts immunological response. MCP-1, a C-C chemokine and MIP-2, a C-X-C chemokine were tested and measured in the sera of infected animals, after 1, 10, 20, 30, 40, 50 and 60 days postinfection, by ELISA method. The diaphragm/muscle and the masseters of the infected mice, were tested for inflammatory response. We found that MCP-1 was partially inhibited by L-mimosine, while MIP-2 was totally inhibited. Moreover, in sections of the diaphragm and masseters, the infiltration of inflammatory cells such as macrophages, lymphocytes and eosinophils were more intense in untreated animals compared to those treated with L-mimosine. These findings show, that L-mimosine may have an inhibitory effect on MCP-1 and MIP-2 serum levels in Trichinellosis and may influence the recruitment of inflammatory cells and the intensity of the inflammatory reaction in this parasitic disease.