Paolo Felaco

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-γ 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.

Toward personalized hemodialysis by low molecular weight amino-containing compounds: future perspective of patient metabolic fingerprint

BACKGROUND L-carnitine deficiency is commonly observed in chronic hemodialysis patients, and this depletion may cause clinical symptoms like muscle weakness, anaemia, and hypotension. MATERIALS AND METHODS We pursued a targeted metabonomics investigation in 28 hemodialysis patients (13 non diabetics and 15 diabetics) and in 10 age-matched healthy controls, on plasma levels of all carnitine esters and of several amino acids. Samples were taken before and after the first hemodialysis treatment of the week. Multiplexed data were collected in LCMRM (Multiple Reaction Monitoring) and analysed by unsupervised multivariate analysis. RESULTS In diabetic uremic patients, we observed lower values of propionylcarnitine than in other groups, while acylcarnitine concentration was higher in uremics compared to controls. The hemodialysis session induced a decline in free, short-chain, medium-chain and dicarboxylic acylcarnitines, whereas the long chain acylcarnitines remained unaffected. Plasma levels of amino acid proline, ornithine, citrulline and serine were significantly elevated in uremic patients before dialysis compared to controls. For most tested plasma amino acids, a significant reduction after hemodialysis session was found. DISCUSSION Our study is the first that investigated on possible modifications of the system of carnitine in diabetic patients in hemodialysis not only in relation to the condition of deficiency but also compared to lipid and glucose homeostasis alteration typical of diabetics. We proposed the application of targeted metabolic fingerprint in the management of the hemodialysis patients.

Adsorption and carbonylation of plasma proteins by dialyser membrane material: in vitro and in vivo proteomics investigations.

BACKGROUND Protein carbonylation is an irreversible and not reparable reaction which is caused by the introduction into proteins of carbonyl derivatives such as ketones and aldehydes, generated from direct oxidation processes or from secondary protein reaction with reactive carbonyl compounds. Several studies have demonstrated significantly increased levels of reactive carbonyl compounds, a general increase in plasma protein carbonyls and carbonyl formation on major plasma proteins in blood from uremic patients, particularly those undergoing chronic haemodialysis. MATERIALS AND METHODS In the present preliminary study, we first assessed by an in vitro filtration apparatus the possible effects of different materials used for haemodialysis membranes on protein retention and carbonylation. We employed hollow fiber minidialyzers of identical structural characteristics composed of either polymethylmethacrylate, ethylenevinyl alcohol, or cellulose diacetate materials. Protein Western Blot and SDS-PAGE coupled to mass spectrometry analysis were applied to highlight the carbonylated protein-binding characteristics of the different materials. We also investigated in vivo protein carbonylation and carboxy methyl lisine-modification in plasma obtained before and after a haemodialysis session. RESULTS Our data underline a different capability on protein adsorption associated with the different properties of the filter materials, highlighting the central buffering and protective role of serum albumin. In particular, polymethylmethacrylate and cellulose diacetate showed, in vitro, the highest capacity of binding plasma proteins on the surface of the hollow fiber minidialyzers. CONCLUSIONS The present study suggests that biomaterials used for fabrication of haemodialysis membrane may affect the carbonyl balance in chronic uremic patients.

IL-34 A NEWLY DISCOVERED CYTOKINE

In this study we describe some biological effects of IL-34, a newly discovered cytokine. We show that Il-34 stimulates monocyte cell viability and directly modulates the number and function of monocytes and regulates myeloid cell growth and differentiation. Moreover, since IL-34 in mice is involved in osteoporosis, an antagonist of this cytokine could be beneficial for the treatment of this disease.

Inflammatory compounds: neuropeptide substance P and cytokines

Inflammatory diseases represent one of the major causes of morbidity and mortality throughout the world and they affect the functions of several tissues. The pathophysiology of these diseases involves release of many pro-inflammatory mediators such as cytokines/chemokines, histamine, C3a, C5a (complement components), bradykinin, leukotrienes (LTC4, LTD4, LTE4), PAF, and substance P, in addition to anti-inflammatory molecules. Recently, it has been demonstrated that neuroimmune interactions are important in the initiation and progress of inflammatory processes. Substance P is an 11-amino acid neuropeptide that is released from nerve endings in many tissues. It acts via membrane-bound NK1 receptors (NK1R). Inflammatory and neuropeptides such as substance P stimulate the release of chemokines, in particular IL-8, a potent neutrophil chemoattractant. Expression of IL-8 is regulated mainly by the transcription factors NF-kappaB, activating protein-1. Substance P plays an important role in immunological and inflammatory states, and it is a mediator of tissue injury, asthma, arthritis, allergy and autoimmune diseases. In this article, our studies revisited the interrelationship between these two powerful inflammatory compounds: substance P and cytokines. These observations suggest that these inflammatory molecules may represent a potential therapeutic target to treat several inflammatory states.

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 bodys 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.

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.

PGD2, IL-1-Family Members and Mast Cells

Cytokines are immunomodulatory and inflammatory compounds produced by many different cell types. The IL-1 family consists of at least eleven cytokines including IL-18 and IL-13 and are essential to the host defence against severe infections and mediate inflammation. IL-18 also enhances tumour rejection and has high capacity to augment the cytotoxicity of NK cells and T cells. IL-33 stimulates basophils and mast cells to produce cytokines and histamine independently of IgE. Mast cells play a crucial role in the development of allergy through the cross-linking of their surface receptors for IgE leading to degranulation and inflammation. Activated mast cells induce the generation of PGD2, detectable in 2–15 minutes after challenge, and LTC4. Here we review the interrelationship between PGD2, IL-1 family members and mast cells.

Tumor Necrosis Factor-Alpha and Mast Cells: Revisited Study

Mast cells reside in connective tissues and are widely recognized as effector cells important in innate and acquired immunity. These cells are the only ones capable of storing preformed TNFα in their cytoplasmatic granules and release upon activation. TNF-alpha is a potent multifunctional cytokine involved in autoimmune diseases, cancer, allergy, and acute and chronic inflammation. In this study, we revisit the interrelationship between TNFα and mast cells.

Inter-Relationship between Chemokines and Mast Cells

The inflammatory response is mediated by immunological and chemotactic factors, proteins of the complement system, histamine, serotonin, arachidonic acid products and cytokines. All these compounds, including cytokines/chemokines, are major contributors to the symptoms of inflammation. Cytokines/chemokines, commonly referred to as “biological response modifiers”, are relatively new compounds for possible use in stimulation of the immune response, and display a number of overlapping abilities to stimulate cells of various lineages and differentiation stages; nonetheless, most of these compounds are potent inflammatory mediators. Mast cell mediators are either contained within secretory granules or can be synthesized de novo and can be released upon activation by either a massive degranulation, or by a selective release of specific molecules. These cells accumulate in the stroma of a variety of inflamed and transformed tissues in response to locally produced chemotactic factors for immune-cells, such as RANTES and MCP-1. Here we describe some connections between mast cells and chemokines.