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In our societies, the increase of the frequency of the diseases of overweight, in particular obesity, diabetes type 2 and metabolic syndrome, coincides with that of the urinary lithiasis. Like the lithiasic disease, the metabolic syndrome or syndrome X is multi-factor. Several epidemiological studies were interested in research of a physiopathological relation between the various components of this syndrome (obesity, arterial hypertension, diabetes, dyslipemy) and lithogenesis. During the metabolic syndrome, resistance to insulin and the defect of renal ammoniogenesis constitute the principal disorders supporting lithogenesis. The defect of renal ammoniogenesis armature by the resistance of the renal cells to insulin involves a urinary hyperacidity which supports the crystallization of the uric acid responsible for the formation of uric or mixed uric acid/oxalate stones.

Background: Psoriasis is a chronic inflammatory cutaneous disorder. It is marked by aberrant epidermal and dermal expression of cytokines., Aim: Evaluate the expression of proinflammatory cytokines in a particular severe form of psoriasis the psoriatic erythroderma., Methods: We focused on intra-lesional cytokine gene expression in cutaneous biopsies of lesional site and their correspondent non lesional skin. On the whole, four healthy volunteers and thirty six patients were included in this study. Among these, three had a psoriatic erythroderma. Assuming that local production of cytokines may be approached by mRNA cytokine quantification, the expression of alpha tumour necrosis factor (TNFalpha) and interleukin-8 (IL-8) was analyzed by reverse transcription and real time quantitative polymerase chain reaction., Results: Under expression of all selected molecules in psoriatic erythroderma lesions was contrasted with the data obtained in the other psoriatic lesion forms witch revealed that ratios had significantly increased in lesional skin compared with non lesional one. However, at anatomy-pathology analysis, inflammatory infiltrate in psoriatic erythroderma was classical poor and no specific of this disease, such as the case of our three patients. This could explain the drop of intra-lesional inflammatory mediators., Conclusion: The paradoxal low levels of proinflammatory cytokines in psoriatic erythroderma are an original and important result.

Introduction: The semicircular lipoatrophy of the thighs is a disorder whose incidence remained rare for years. Only recently, an "epidemic" situation emerged, affecting hundreds of subjects who shared a status of administrative employee., Observation: The older etiopathogenic hypotheses give way to a newer one implying the electromagnetic fields generated by computers and their wirings. The resulting modifications in the intrinsic bioelectrical properties of the skin could influence the biology of macrophages exhibiting lipophagic activity in the hypodermis. The electroactivation of these cells could lead to TNF-alpha release., Discussion: The semicircular lipoatrophy of the thighs is a problem that may affect an employee out of two. Rather than hoping an efficaceous drug therapy, prevention must be advocated by adapting the work conditions related to the use of computerized devices.

Lnk is an adaptator protein involved in B lymphocytes and platelet differentiation and in T lymphocyte activation. We previously reported on Lnk expression and regulation in endothelial cells (ECs) upon activation. In the present study, the involvement of Lnk in the tumor necrosis factor alpha (TNFalpha) pathway was investigated in vitro through Lnk overexpression in primary cultures of human endothelial cells. Using a recombinant adenovirus encoding human Lnk, we first demonstrated that Lnk overexpression does not induce vascular cell adhesion molecule-1 (VCAM-1) suggesting that Lnk does not promote ECs activation. However, Lnk overexpression significantly reduced TNFalpha-mediated expression of VCAM-1 (at mRNA and protein levels) in activated EC as compared with controls. Western blot analysis showed that Lnk overexpression in HUVEC was associated with phosphorylation of Akt kinase (at Ser 473) with no effect on IkappaBalpha, the specific inhibitor of NFkappaB, indicating that Lnk promotes activation of the phosphatidylinositol 3-kinase (PI3-kinase) pathway in ECs. Altogether, these results suggest that, in ECs, Lnk may participate to a regulatory pathway involving the PI3-kinase and modulating the inflammatory response.

AMONG THE BIOLOGICAL MEDIATORS OF INSULIN RESISTANCE: two compounds released by the adipocyte are found, such as free fatty acids and tumor necrosis factor-alpha. They are incriminated in the deleterious role of visceral adiposity on the metabolic parameters. INTRA-CELL CORTISOL: Attention is also focused on the potential implication of cortisol in the genesis of metabolic syndrome, because cortisol is a potent antagonist of the effect of insulin and its presence in excess enhances visceral obesity and insulin resistance. GENETIC ASPECTS: Although no major locus has yet been identified, recent findings of several mutations or polymorphisms in genes acting in different regulation systems (adiponectin, PPARgamma2) also provide an interesting insight into the pathogenesis of this syndrome. Moreover, there is growing epidemiological evidence that intra-uterine factors could induce a so-called programming of the individual that may, at least in part, account for the difficulties encountered by the classical genetic approach.

Obesity is a risk factor for type 2 diabetes and cardiovascular diseases. The hypothesis that cytokines could play a role in the pathophysiology of obesity and insulin resistance is suggested in the last few years. We showed a positive correlation between circulating interleukin (IL-6) levels and obesity and insulin resistance suggesting that IL-6 could be involved in insulin resistance in humans. We showed a decrease of both circulating and adipose tissue IL-6 levels in non-diabetic obese subjects after a very low calorie diet program inducing weight loss. This suggests that adipose tissue could be involved in the regulation of circulating IL-6 levels in these subjects. Adipose tissue is also involved in lipodystrophies particularly in HIV patients on antiviral therapy. We showed an alteration of the SREBP-1 transcription step in subcutaneous abdominal adipose tissue from HIV patients. We found an inverse correlation between circulating adiponectin levels and both insulin resistance and cardiovascular risk factors such as CRP levels and apolipoprotein B/A1 ratio. These findings suggest that adipose tissue is involved in insulin resistance in humans particularly via adipocytokine secretion., (Copyright John Libbey Eurotext 20003.)

Pathophysiology of deeply infiltrating endometriosis remains controversial whereas physiopathologic mechanism of superficial endometriosis is nearly demonstrated. Superficial peritoneal implants derive from adhesion and proliferation of endometrial cells regurgitated in peritoneum with retrograde menstruation. Peritoneal inflammation involving cytokines as TNFalpha and aromatase over-expression might be involved in the endometriosis invasion processus. Specific molecular defects of both eutopic and ectopic endometrium have been identified for each of the processes involved in the disease development. Aromatase inhibitors decrease endometriosis lesions in a mouse model of endometriosis which was induced surgically. Few studies report efficacy of aromatase inhibitors in human endometriosis. Theoretically, aromatase inhibitors should not be used alone in premenopausal women because of the resultant increase in gonadotropin levels. Nevertheless, in premenopausal women, aromatase inhibitors may be used in association with Gn-RH agonists. TNFalpha is a secretory factor of macrophages that is known to be increased in the peritoneal fluid of women with endometriosis. Granulosa cells from these women produce higher levels of TNFalpha. This cytokine can stimulate adhesion and proliferation of endometrial cells and enhances metalloproteasis expression, making thus endometrial cell invasion easier. It also stimulates angiogenesis by regulating expression of IL-8. TNFalpha is also cytotoxic to gametes. In mice and baboon models with induced endometriosis, anti-TNFalpha (TNF binding protein-1) decreases AFS score stage and reduces in size the endometriotic foci. No clinical assay has studied TNFalpha efficacy on human endometriosis.

Although cytokine activation has long been recognized to associate with cardiac ischemia and reperfusion, the concept that these cytokines may enhance some cardioprotective mechanisms has only recently been considered. Ischemic preconditioning is a biologic phenomenon that activates innate cytoprotective programs in the heart. Ischemic preconditioning has been described where a transient non-lethal ischemic "trigger" or endogenous molecules produced/released by ischemia enables the tissue to become more resistant/tolerant to subsequent potentially lethal ischemia. The mechanisms and signalling events involved in this cytoprotective program still remain obscure. Recently, it has been suggested that cytokine activation including tumour necrosis factor (TNF alpha) may play a key role in the preconditioned phenotype. Moreover, new studies have given the evidence that the exploration of cytokine-activated sphingolipid signalling pathways may enhance our understanding of the preconditioning program.

Adipose tissue is not simply a store of excess energy, but also secretes a variety of proteins into circulating blood that influence systemic metabolism. These include tumor necrosis factor (TNF-alpha), plasminogen activator inhibitor type 1 (PAI-1), leptin, resistine and adiponectin. These are collectively known as adipocytokines. Adiponectin (also referred to as AdipoQ, Acrp 30, apM1 or GBP28) is a novel adipose-specific protein. A recent genome study mapped a susceptibility locus for type 2 diabetes and the metabolic syndrome on chromosome 3q27, where the adiponectin gene is located. Adiponectin is a peculiar adipocytokine because in contrast to the markedly increased levels of many others, as leptin or TNF-alpha, its level is reduced in obesity and type 2 diabetes. The administration of thiazolidinediones, which are synthetic PPARs-gamma ligands, significantly increases the plasma adiponectin concentrations, an effect that could improve insulin sensitivity. Thus, the administration of adiponectin may provide a novel treatment modality for insulin resistance and type 2 diabetes.

Hashimoto's encephalopathy (HE) is a rare neurological complication of chronic lymphocytic thyroiditis. As its clinical presentation is aspecific, other etiologies of acute encephalopathy have to be ruled out. We report the case of a 29-year old woman with neuropsychiatric signs preceding coma, myoclonus and epileptic seizures. Clinical and electroencephalographic features were consistent with the diagnosis of new variant of Creutzfeldt-Jakob disease. However, high titres of antithyroid antibodies in serum directed towards the diagnosis of HE. Despite oral steroids, the patient died five months later. Neuropathological findings ruled out spongiform encephalopathy and disclosed aspecific activated microglia. Our observation suggests that this process could be involved in the pathogenesis of HE. Even in the absence of clinical dysthyroidism, HE diagnosis has to be suspected in the settings of acute encephalopathy associated with seric antithyroid antibodies.

Unlabelled: 1. EPITHELIUM OF THE MIDDLE EAR: The middle ear has a respiratory type epithelium. The mucus is produced by mucosal and by submucosal cells in the Eustachian tube. 2. LYMPHOID TISSUE: The defensive barrier of the mucosa is potentialized by lymphoid tissue in the middle ear that produces a local specific immune response. Bacterial and viral antigens can induce an inflammatory reaction. 3. TUBOTYMAPNIC CAVITIES: The humoral immune system (B lymphocytes) secreting IgG, IgA and IgM) and cell mediated response (T lymphocytes) are active in the tubotympanic cavities. 4. MAST CELLS: Present in contact with vessels and nervous fibers of the tubotympanic chorion, mast cells are activated by IgE linkage to antigens, leading to local allergic inflammatory phenomena with production of histamine, C leukotrienes, platelet activating factor (PAF) and cytokines. 5. MAINTAINING OPEN CAVITIES: During the inflammatory reaction, mucus-secreting cells are stimulated and their glycoprotein secretions are modified. Since the middle ear epithelium has a water-absorption action contributing to aeration of the middle ear cavities. 6. CYTOKINE RESPONSE: During acute middle ear otitis, cytokines secreted in response to bacterial and viral lipopolysaccharides include tumor necrosis factor alpha (TNFa) which plays a crucial role: induction of fibroblast proliferation, activation of polymorphonuclears, inhibition of vascular endothelial tissue and B lymphocytes. It facilitates healing of the middle ear infection, but an also induced pathological lesions in case of incomplete repair. 7. BACTERIAL FLORA: Haemophilus influence, Branhamella catarrhalis, and Streptococcus pneumoniae colonize the respiratory epithelium of the middle ear via the Eustachian tube, generally after viral infection. 8. GLUCOCORTICOIDS: Administered before injection of a bacterial endotoxin, glucocorticoids significantly reduce inflammatory phenomena in acute otitis induced in rat models. In acute middle ear models in the guinea pig, corticosteroids reduce lipoperoxidation; free radicals are the cause of the persistence of inflammation in the acute middle ear. 9. NEUTROPHIL MIGRATION: Antibodies blocking cell adhesion molecules (CAM), or instance antiCD11 B and antiCT 18, inhibit polymorphonuclear migration, and could be very useful for the treatment of acute middle ear infection. Use of prostaglandin inhibitors does not significantly reduce the risk of residual effusion at 10 and 30 days after the acute episode. 10., Clinical Trials: There is a significant body of scientific evidence proving the efficacy of combining antiinflammatory drugs and antibiotics for first line treatment of middle ear infection to prevent seromucosal otitis.

Cytokines such as IL-1 or TNF-alpha induce a specific cellular responses through the activation of a transcriptional factor, NF kappa B. This activation requires the phosphorylation of an inhibitory subunit, I kappa B, which relies upon an intracellular production of reactive oxygen intermediates. Peroxides, but also the increase of the GSSG/GSH ratio are assumed to play a major role in this process. There is presently a good agreement on the overall scheme of IL-1 and TNF-alpha activation and on the involvement of reactive oxygen intermediates in the corresponding signal transduction cascades. However several questions regarding the molecular mechanisms involved in particular steps of these cascades remain largely unresolved: how and at which subcellular level, do the cells produce these reactive oxygen intermediates that will contribute to NF kappa B activation in response to IL-1 or TNF-alpha? What are the kinases/phosphatases, being modulated by peroxides and what is the contribution of high GSSG levels to NF kappa B activation? In this paper, we will briefly overview this basic issue in cell biology and highlight some of the recent experimental data that will help us to understand the exact role of reactive oxygen intermediates in NF kappa B activation and the molecular mechanisms involved.

Many clinical and experimental data are in favour of a participation of leukocytes in vascular disease. Diabetes, a risk factor, is associated with a dysfunction of neutrophils. If chemotaxis and phagocytosis are deficient, it is not clearly established whether superoxide generation is conserved in these patients. We have measured this function in 35 noninsulin dependent diabetic patients, compared with a control population. We have assessed, in parallel, a profile of the cytokines involved in vascular phenomenons including TNF alpha, IL-1 beta et IL-6. Our results indicate that the generation of free radicals is normal in diabetics, with a significant elevation of TNF alpha. These results suggest a possible participation of this cytokine in the modulation of granulocyte reactivity.

The possible role of tumor necrosis factors (TNF) in autoimmunity led us to explore the relationship between TNF production, polymorphism of the TNF-beta gene and type one diabetes. In the diabetic group we found a low production of TNF-beta. This abnormality appeared not to be exclusively related to the TNF-beta gene and could be also due to polymorphic regulatory sequences in the major histocompatibility complex region.

A large number of cytokines are found within foci of inflammation. Two of these cytokines, namely interleukin-1 (IL-1) and tumor necrosis factor (TNF), play a key role in orchestrating the mechanisms responsible for inflammation. These two cytokines induce production by many cells of lipid mediators, proteases, and free radicals, all of which play a direct role in development of the deleterious effects of inflammation. IL-1 and/or TNF exert cytotoxic effects on the vascular endothelium, cartilage, bone, muscle, or pancreatic beta-cell islets. Cytokines, including interferon gamma (IFN), IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF), amplify the inflammatory response by increasing production of IL-1 and TNF by macrophages. Macrophages also produce other cytokines, such as IL-8 and macrophage chemoattractant protein-1 (MCP-1), with chemoattractant properties that contribute to draw leucocytes to the site of inflammation. IL-6, produced in large amounts during inflammatory processes, induces the production of acute phase proteins by hepatocytes. IL-1, TNF, IL-11, leukemia inhibitory factor (LIF), and transforming growth factor beta (TGF beta) share this effect. TGF beta also has a number of anti-inflammatory effects. TGF beta, IL-4, and IL-10 inhibit production of IL-1 and TNF. Glucocorticoids also have this effect. Glucocorticoids can be produced as a result of a chain of events initiated by IL-1, TNF, and IL-6 and involving the neuro-endocrine axis. Other substances, such as IL-1 receptor antagonist (IL-1 ra) or soluble forms of the TNF receptors, can specifically inhibit the effects of IL-1 and TNF. Cascade production of cytokines, inhibition, negative feed-back, and synergistic mechanisms are parameters that illustrate the concept of "cytokine network" and aptly characterize the role of these mediators in the mechanisms of inflammation.

Tumor necrosis factor alpha (TNF alpha) and interleukins (IL) are the principal cytokines involved in the clinical and biological manifestations of septic shock. Their secretion are triggered mainly by endotoxin, but products of Gram positive cocci as well as of virus or of parasites are equally effective. Cytokines represent a normal protective defense against infection, but an excessive production have toxic effects. In experimental models of endotoxinemia, TNF alpha is the first cytokine produced, then IL-1 and IL-6. Other inflammatory mediators are secreted later. Thus it seems logical to try to modulate cytokine production or actions. However, several questions remains since experimental data are sometimes not applicable too human diseases, cytokines are organised in a network with several interaction. It is too early to propose routine anti-cytokines drugs in septic shock.

TNF alpha is generated in inflammatory lesions of the glomerulus. Both resident mesangial cells and infiltrating macrophages contribute to this generation, when exposed to bacterial lipopolysaccharide and immune complexes, respectively. TNF alpha has multiple actions on glomerular cells and on distant target cells that appear to promote in turn either amplification or limitation of TNF alpha release and TNF alpha binding. For instance, there is in vitro evidence that locally generated reactive oxygen metabolites: 1) cause increased release of TNF alpha into the extracellular space by accelerating the cleavage of its cell-associated precursor, and 2) reduce the expression of both cell-associated and soluble TNF alpha receptors. Thus it might be expected that reactive oxygen metabolites released at the site of glomerular inflammation limit autocrine, juxtacrine and paracrine effects of TNF alpha and simultaneously increase its widespread release into the circulation.

The IL6 and TNF alpha specific mRNAs are expressed in normal human kidney; IL6 protein can be detected in normal glomerular mesangium by immunochemistry while TNF alpha is not present. Increased expression of IL6 mRNA is found within the glomeruli in mesangioproliferative glomerulonephritis and IL6 protein is detectable in proliferating mesangial areas. TNF alpha is mainly detected in infiltrating macrophages. During acute rejection episodes de novo expression of TNF alpha appears in renal transplant tubular epithelial cells as well as that of HLA class II antigens, ICAM-1 and VCAM-1 molecules. In renal cell carcinomas, the tumoral cells produce in vivo and in vitro IL6 and TNF alpha at the mRNA and protein levels. Therefore parenchymatous renal cells can produce IL6 and TNF alpha in various pathological conditions. However the mechanisms which regulate the production of these cytokines as well as their role in the genesis or the amplification of tissular damage remain to be elucidated.

Originally described for its capacity to induce hemorrhagic necrosis of transplantable tumors in mice, TNF-alpha also exerts cytotoxic effects against some tumor cell lines in vitro. It is now known that TNF is an essential mediator of cellular immunity and a wide variety of biological activities of TNF in vitro and in vivo has been reported. TNF is an important mediator of inflammation and is involved during the pathogenesis of several auto-immune, infectious or cancer diseases. While some immunomodulatory properties of TNF have at least been partially elucidated, the biochemical basis of TNF cytotoxic action remains largely unknown. Furthermore, the molecular mechanisms of TNF susceptibility have yet to be clarified. Clinical studies with recombinant TNF as an anticancer agent are encouraging. Multiple phase I and phase II trials have been carried out without major therapeutic effect. In fact, TNF resistance and TNF-induced systemic toxicity are two major limitations for the use of TNF as an antineoplastic agent. The clinical application of human TNF remains an area of active research and innovative approaches such as gene therapy need to be elaborated. The elucidation of the process of lysis and the modulation of TNF resistance are crucial to the future development of TNF and its use in antitumor therapy.

Levels of TNF alpha, IL-6-, soluble R IL-2, and fibronectin, were evaluated in fifteen patients with cerebral malaria. Relations between cytokines levels and parasitemia were assessed. Concentration of IL-6, and soluble R IL-2, correlated with parasitic density on admission. It was appeared, that IL-6, would be a prognostic factor, as interesting as TNF alpha.

Septic shock remains an acute condition with a bad prognosis and a high mortality rate. This could be related to our incomplete understanding of the pathophysiological mechanisms involved, especially in the immunological field. Recently, several studies have stressed the key role of cytokines. Amongst these, the tumour necrosis factor (TNF) seems to be the most important. This peptide is a hormone secreted by monocytes and macrophages under the effect of various stimuli such as lipopolysaccharides or endotoxin. Giving TNF mimicks the clinical and biological patterns of septic shock. Moreover, high concentrations of TNF have been found in patients suffering from septic shock. Pretreatment with monoclonal antibodies against TNF prevents the occurrence of septic shock after endotoxin administration. TNF acts directly via ubiquitous specific receptors; this probably explains its diffuse activity. The therapeutic implications of these recent advances are not clear. It is not known, for the moment, whether TNF secretion is beneficial or deleterious for the patient.

One of the major side effects induced by the in vivo administration of the murine monoclonal antibody OKT3 is a spontaneously reversible clinical syndrome associating in variable proportions depending on the patient: fever, chills, headaches, diarrhea and seldomly meningismus. Sera from 3 renal allograft recipients treated with OKT3 were studied and showed that a massive although transient release of some cytokines namely, Tumor Necrosis Factor alpha, Interleukin 2 and Interferon gamma is observed following the first OKT3 injection.