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Insulin resistance is a key pathophysiologic feature of obesity, type 2 diabetes mellitus and prediabetic states (impaired fasting glucose, impaired glucose tolerance). TNF-alpha, a proinflammatory cytokine, plays an important role in the pathogenesis of insulin resistance associated with inflammation during the course of rheumatic diseases. Therapies aimed at neutralizing TNF-alpha, such as the monoclonal antibody infliximab, represent a relatively new approach in the treatment of rheumatic diseases and allow to obtain significant results in terms of control of the inflammatory process. In this article we reviewed the scientific evidence published in the literature about a potential role of TNF-alpha blockade in improving insulin resistance in rheumatic patients without diabetes.

Recently, a new member of the TNF family, BLyS, was identified. This protein, synthesized by myeloid cell lines, specifically interacts with B lymphocytes and increases their life-span. BLyS was studied in the murine models of some autoimmune diseases and it was demonstrated that it has a key role in the B lymphocyte system homeostasis and in the relation between chronic inflammation and autoimmunity. Analysis of BLyS plasma levels in Systemic Lupus Erythematosus, Sjogren's Syndrome and Rheumatoid Arthritis (RA) has shown that BLyS is higher in a group of patients than in the controls. In RA, BLyS correlates with the disease activity, in particular, with the swollen joints count; so, at least part of the chronic rheumatoid synovitis could be the epiphenomenon of the B cells activation driven by monocyte-macrophage population. More studies are necessary to understand the role of BLyS in the interaction between the monocyte and the B lymphocyte in some autoimmune disease and the possible usefulness of this cytokine as a diagnostic or prognostic marker and/or therapeutic target.

Many study in literature have suggested a possible role of T cells and tumor necrosis factor-alpha (TNF-alpha) in the pathogenesis of bone loss that occurs in pathological conditions, such as systemic inflammatory diseases; the molecular bases through which this phenomenon occurs and the relevance of this mechanism also in estrogen deficiency induced bone loss remain unclear. In our study we observed that TNF-alpha knock-out mice (TNF-/-), as well as transgenic mice without thymus (and therefore without mature T cell), do not lose bone after ovariectomy like observed for mice of normal genetic background (wild type, WT). Moreover, after transfer into athymic mice of T cell isolated from WT ovariectomized animals (and so stimulated by estrogen deficiency to proliferate and to produce TNF-alpha), ovariectomy recovers its ability to induce bone loss; whereas there is no change in bone density after injection into athymic mice of T-cell purified from TNF-/- animals which, even if mature, are unable to produce TNF-alpha. Therefore the presence of TNF-alpha producing T-cell is essential for estrogen deficiency to influence bone metabolism. In the following study of the research group of Prof. Pacifici it has been shown that the increased activation of TNF-alpha producing T-cell in the ovariectomized mice is due to increased INF-gamma levels, resulting from ovariectomy-induced enhanced secretion of IL-12 and IL-18 by macrophages. INF-gamma promotes expression in immunocompetent cells of class II transactivator (CIITA), that, up-regulating expression of the major system of histocompatibility of class II, makes the macrophages more active in antigen presentation to T-cells, which in turn start producing TNF. For the first time an immune mechanism is involved in the pathogenesis of post-menopausal osteoporosis; nevertheless the applicability of these conclusions also in humans remains still to be proved.

Hypercholesterolemia and overt atherosclerotic disorders have been associated with a low-grade inflammation that involves not only the intrinsic cells of the artery wall, but also circulating cells. Platelets as well as monocytes participate importantly in this disease process through the release of a wide variety of biologically active substances. Recent findings on the inflammatory actions of platelets have opened new perspectives in the comprehension of the pathogenetic mechanism(s) of atherosclerosis. Stimulated platelets, in fact, actively synthesize proinflammatory cytokines which have been all involved in the inflammatory process associated to hypercholesterolemia and plaque development. In this context, increasing evidence suggests that interrelated inhibition of inflammation and thrombosis induced by statins could largely contribute to clinical benefits from lipid-lowering therapy.

The management of rheumatoid arthritis (RA) has changed considerably during the past 15 years. Current strategies emphasize the need for early diagnosis and therapeutic intervention based on the use of disease modifying antirheumatic drugs (DMARDs). More than a dozen drugs or drug classes of DMARDs are currently in common use in RA. After a long hiatus, drug development for RA resumed a few years ago with the introduction of Leflunomide and the biologic agents. Unlike the older DMARDs (apart from the cytotoxics) the newer drugs were designed with strict reference to RA pathophysiology and the intended action of these agents is highly likely the explanation for the observed efficacy. Proinflammatory cytokines, such as interleukin-1 (IL-1) and Tumor Necrosis Factor (TNF), play an important role in maintaining the chronicity of RA and mediating tissue damage. TNF antagonists have rapidly emerged as a valuable class of antirheumatic agents. Etanercept, a dimerized version of the soluble TNF receptor II, and infliximab, a chimeric anti-TNF monoclonal antibody, are currently approved in our country for the treatment of refractory RA in the frame of ANTARES Project. Other two biologic agents, adalimumab, a fully humanized anti-TNF monoclonal antibody, and anakinra, a recombinant human IL-1 receptor antagonist, will be also soon available. It is recommended to initiate pharmacological treatment with an effective DMARD early in the course of the disease. Biological therapies have the potential to revolutionize the treatment of RA; however the use of TNF blocking agents as the first DMARD for the treatment of RA should, at present, be limited, because these compounds are expensive and one needs to include cost considerations along with those of efficacy, effectiveness and long-term safety.

The inflammatory response to microcrystals is one of the most powerful and intriguing examples of inflammation observable in man. Although many mechanisms of this reaction are well known, some aspects need to be further clarified, in particular those related to the self-limited nature of the process. Type and duration of the inflammatory reactions are mainly influenced by crystals characteristics, including shape and size, which, in turn may involve the crystal- binding of several proteins, essential for the modulation of cellular responses. Cells most involved in the acute attacks are macrophage and neutrophils, which are responsible for the secretion of several important mediators of inflammation, such as prostaglandins and cytokines. These substances may in turn influence both intensity and duration of the acute attack. The proinflammatory effects of interleukin (IL)-1, IL-6, IL-8 and tumour necrosis factor (TNF)-alpha are counterbalanced by the anti-inflammatory activity of transforming growth factor (TGF)-beta, which may inhibit both the cell recruitment and cytokine synthesis. The role of TGF is crucial, not only by limiting acute inflammation but also by promoting formation and deposit of calcium crystals. However, the final effect of the balance between inflammatory and anti-inflammatory cytokines may also depend by other tissutal and cellular factors, not all of which are still completely understood.

Excessive biohumoral activation participates in the pathophysiology and progression of congestive heart failure (CHF). Pharmacological inhibition of the renin-angiotensin-aldosterone and beta-adrenergic systems improves the mortality and morbidity of this disease. Among other detrimental molecules, two local factors, tumor necrosis factor (TNF)-alpha and endothelin (ET) both contribute to the worsening of CHF. TNF-alpha can induce many of the cellular modifications typically associated with CHF, such as myocyte death, interstitial tissue derangement and negative inotropism. On the other hand ET promotes vasoconstriction, and cell growth and proliferation. On the premise of some favorable experimental studies, selective antagonism of TNF-alpha or ET has been tested in clinical trials in order to control the progression of or even reverse CHF. However, contrasting results have been obtained so far with either approach, in accordance with other unfavorable data from animal models of heart failure. Etanercept (Enbrel, a recombinant dimer of two p75sTNFR molecules fused to the Fc fragment of human IgG1) has proved to be useful and effective in basic and animal experiments, while contrasting data have been reported on humans. The Randomized EtaNErcept Worldwide evALuation (RENEWAL) trial has recently been prematurely stopped due to impossibility of showing statistically significant results with the pre-specified sample size. Results of phase II to III clinical trials on different ET receptor antagonists in CHF have yielded conflicting results, so that none of the agents of this class have been labeled for CHF. The mechanisms by which TNF-alpha and ET might exert their negative biological actions are discussed together with an analysis of the possible reasons why they have failed so far in human CHF.

Tumor necrosis factor alpha (TNF alpha) is a cytokine with proinflammatory properties which produces negative inotropic effects on the heart. It is produced in a variety of conditions such as septic shock, acute myocarditis, reperfusion injury, and congestive hear failure (CHF). This production is probably due to activation of immune elements localized in the heart or periphery, or both. TNF alpha acts by binding to two specific receptors: TNF-R1 and TNF-R2. These two proteins have different effects. TNF-R1 has cytotoxic and antiviral activity, induces fibroblast proliferation, and mediates apoptosis. TNF-R2 is involved in septic shock and in lymphocyte proliferation. They both have negative inotropic effect on the heart. It has been showed that these receptors are down-regulated in congestive heart failure, while their soluble forms (sTNF-R1 and sTNF-R2) increase with the severity of symptoms. However the significance of this increase is still unclear. The role of Fas, a receptor protein that induces apoptosis, is also examined. Fas and its ligand have homologies respectively with TNF alpha and TNF-R. Also the soluble form of Fas (sFas) increases in relation to heart failure and is related to soluble forms of the similar receptor family, therefore it is possible that the same stimuli lead the three receptors to act together. SFas, as well as sTNF receptors, may play an important role in CHF.

The formation of new vessels, (angiogenesis) characterizes body development and is pivotal in some diseases. In particular, angiogenesis is crucial for the growth of tumors and metastasis diffusion. The beginning of tumor angiogenesis is caused by the selection of a cancer cell clone which induces an unbalance between inducers and inhibitors of angiogenesis. The inhibition of this process by natural or chemical compounds increases apoptotic index in the tumors, does not causes drug resistance and has been demonstrated to induce cancer dormancy in many animal models.

In the past few years tumor necrosis factor (TNF), also known as cachectin, has been isolated, cloned and now human recombinant TNF is available. This cytokine has numerous actions, which can be divided into four groups: 1) antitumor function; 2) immunomodulating activity and function in the inflammatory response; 3) effects on metabolism; 4) other functions. TNF was first identified for its anticancer activity; it is able to induce hemorrhagic necrosis in subcutaneously implanted tumors, due to the induction of free radicals in tumor cells and to vascular damage. It can also activate T-lymphocytes to become lymphokine-activated killer cells (LAK cells) against tumors. TNF also plays an important role in the inflammatory response: it mediates many of the immunologic features of T-cell function and of infection, and is essential in septic shock. TNF is a cause of the hypertriglyceridemia and the cachexia that characterize chronic infections and neoplasms. In vitro this cytokine causes growth of vascular endothelial cells; this observation suggests that it could have an atherogenic role. In in vivo experiments severe hepatic ischemia-reperfusion injury results in TNF release with subsequent local and systemic injury that was significantly reduced by anti-TNF antiserum pretreatment. Thus, TNF could be a cause of ischemic tissue damage. In conclusion, while TNF is known to play many roles, the intercellular network of the cytokines is not yet sufficiently understood and so we are only just beginning to comprehend the full implication of this important molecule in both histology and pathology.

Tumor necrosis factor (TNF) and interleukin-1 (IL-1) are soluble factors that play a pivotal role in acute and chronic inflammation. TNF is a 17 Kda protein mainly released by monocytes and macrophages and is a common mediator of toxic shock, cachexia and tumor necrosis. IL-1 was first described as a lymphocyte activating factor and it was then discovered that IL-1 has a number of other biological activities and that there are at least two major types of IL-1 (alpha and beta) which bind to the same receptor. Recently it has been shown that TNF and IL-1 beta have an important role in bone resorption.

Human Tumor Necrosis Factor-alpha (TNF-alpha) is a multifaceted cytokine mainly produced by activated monocytes or macrophages. Several recent studies have shown that TNF-alpha can exert a variety of in vitro and in vivo effects including: modulation of normal and malignant haemopoiesis, antineoplastic activity, activation of neutrophils, induction of IL-1 production, hyperpyrexia and induction of cachexia. Furthermore this cytokine is thought to play an important role in the pathogenesis of septic shock. The principal biochemical characteristics and biological activities of this cytokine will be here summarized.