Interleukin-6 as a Director of Immunological Events and Tissue Regenerative Capacity in Hemodialyzed Diabetes Patients.

Hemodialyzed patients have innate immunity activation and adaptive immunity senescence. Diabetes mellitus is a frequent cause for chronic kidney disease and systemic inflammation. We studied the immunological pattern (innate and acquired immunity) and the tissular regeneration capacity in two groups of hemodialyzed patients: one comprised of diabetics and the other of non-diabetics. For inflammation, the following serum markers were determined: interleukin 6 (IL-6), interleukin 1ß (IL-1ß), tumoral necrosis factor α (TNF-α), IL-6 soluble receptor (sIL-6R), NGAL (human neutrophil gelatinase-associated lipocalin), and interleukin 10 (IL-10). Serum tumoral necrosis factor ß (TNF-ß) was determined as a cellular immune response marker. Tissue regeneration capacity was studied using neurotrophin-3 (NT-3) and vascular endothelial growth factor ß (VEGF-ß) serum levels. The results showed important IL-6 and sIL-6R increases in both groups, especially in the diabetic patient group. IL-6 generates trans-signaling at the cellular level through sIL-6R, with proinflammatory and anti-regenerative effects, confirmed through a significant reduction in NT-3 and VEGF-ß. Our results suggest that the high serum level of IL-6 significantly influences IL-1ß, TNF-ß, NT-3, VEGF-ß, and IL-10 behavior. Our study is the first that we know of that investigates NT-3 in this patient category. Moreover, we investigated VEGF-ß and TNF-ß serum behavior, whereas most of the existing data cover only VEGF-α and TNF-α in hemodialyzed patients.

Neurotrophin-3, TNF-alpha and IL-6 relations in serum and cerebrospinal fluid of ischemic stroke patients.

Pro-inflammatory cytokines and neurotrophins in the central nervous system (CNS) have been recognized as mediators of both neurodegenerative and neuroprotective mechanisms in a number of CNS pathologies. A rapid, sustained elevation of these molecules was recently reported after traumatic and ischemic brain injury. Inflammatory mechanisms and immune activation have been hypothesized to play a role in the pathogenesis of cerebral ischemia. Stroke is the third largest cause of death next to heart disease and cancer in the world, and it is an important cause of death and disability in developed countries. Role of excitatory amino acids receptors activation, calcium overload, nitric oxide and oxidative stress in the pathogenesis of ischemic brain damage is well established. Stroke may modulate peripheral neurotrophic factors levels. In experimental animal models, neurotrophin-3 (NT-3) has been shown to be produced by glial cells as an adaptability response to hypoxia. In spite of substantial research and significant number of neuroprotective drugs that have been developed to limit ischemic brain damage and to improve the outcome for stroke patients, no specific therapy for stroke is available. The neurotrophins have been proposed as therapeutic agents for the treatment of neurodegenerative disorders and ischemic injury. In the present work, we investigated the possible correlation of NT-3 with tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in the serum and cerebrospinal fluid (CSF) from patients with ischemic stroke (IS).

Ethanol-induced dysfunction of hepatocytes and leukocytes in patients without liver failure.

The repeated intake of a great amount of ethanol is followed by functional and organic changes in the body. The intestinal absorption of alcohol is accompanied by an increased absorption of Gram negative bacteria endotoxins in the portal blood. In the liver, endotoxins stimulate CD14 receptors on the membrane of Kupffer cells, with a secondary inflammatory liver response, consisting in the secretion of proinflammatory cytokines and acute phase proteins. Simultaneously, alcohol metabolism in the hepatocytes by alcohol dehydrogenase, microsomal enzymes and catalase pathways determines a large production of ROS (reactive oxygen species), with secondary oxidative aggression on all liver cells: hepatocytes, Kupffer cells, endothelial sinusoidal cells, hepatic stellate cells and liver s lymphocytes. The oxidative aggression, as well as the intermediary products of the alcohol metabolism, cause a structural change of the antigenic structures of the liver and of the released proteins, that induces an immune response on the both pathways (humoral and cellular). The pathophysiological mechanisms and the paraclinical characteristics of the ethanol-induced liver failure are well known, so we were interested to study the patients with chronic alcoholism, but no clinical or paraclinical sign of liver failure, in order to describe the liver's protective mechanisms. For this reason, 153 patients with chronic alcoholism were divided into four test lots, in order to determine: the activity and the serum level of ceruloplasmin, plasma level of MDA (malondialdehyde), lactic and pyruvic acids, serum level of transferrin, alpha1-antitrypsin, CRP (C reactive protein), C3 fraction of the complement, IgA, IgG, IgM, IL-1beta, IL-6 and IL-8, cytosolic level of the cytochrome c in the circulating leukocytes. An immunophenotype study (as normal markers) on the peripheral blood lymphocytes was performed, too. The results demonstrate an important oxidative aggression induced by three sources: the alcohol metabolism in the hepatocytes, activated Kupffer cells and activated neutrophils that have infiltrated the liver, due to the chemoattractant effect of IL-8. This aggression induces apoptosis and necrosis of the liver cells. The major liver protective factor is, in our opinion, IL-6, due to its important antioxidant, antiapoptotic and proregenerative demonstrated actions. This protective effect of IL-6 is accompanied by antioxidant and antiprotease actions of ceruloplasmin, alpha1-antitrypsin and transferrin. We consider that an increased serum level of IL-6 accompanied by a decreased level of IL-1beta signify that antiapoptotic, antioxidant and proregenerative liver mechanisms prevail against proapoptotic and necrotic mechanisms. On the other hand, the ethanol-induced apoptosis of leukocytes (especially of the B cells) is very important, probably due to the absence of IL-6 protective action on these cells. The apoptosis of the circulating leukocytes is proved by their significant increase of the cytochrome c cytosolic level. The ethanol-induced liver immune response is predominantly cellular, as proved by the decreased ratio T helper (CD4+)/T cytotoxic (CD8+) in the peripheral blood. It is very important to observe that these significant immunologic changes appear before clinical or paraclinical signs of hepatic failure start. All these parameters were investigated in three groups of patients: chronic alcoholics, chronic alcoholics in the first 24 hours of the withdrawal and chronic alcoholics with acute alcohol intoxication, so the aggression types and the protective mechanisms were measured and differentiated in each "ethanolic status".

Oxidative aggression in atherosclerosis associated to degenerative psychoorganic disturbances.

We had in view the effect of the oxidative aggression as determinant factor in atherogenic process associated with degenerative psychoorganic disturbances. It was studied a group of old people distributed in two subgroups: a) 51 old people with atherosclerosis (AS) and b) 57 old people with atherosclerosis associated with degenerative psychoorganic disturbances determined by chronic ethylism. The results were compared to those of a 40 healthy adults group. Concomitantly, it were evaluated the supervened modifications in the antioxidant defense systems of the organism, by determining both of some nonenzymatic defense system components (reduced glutathione, ceruloplasmine and transferrin) and of some enzymatic defense system components (superoxide dismutase, catalase and glutathione peroxidase). The obtained results emphasize an important aggression exerted by the lipid peroxides against the old people organism, aggression that is amplified by the chronic ethylism with appearance of the degenerative psychoorganic disturbances. Generally, the antioxidant defense capacity of the old people organism is depressed, especially in the group with atherosclerosis associated with degenerative psychoorganic disturbances engendered by excessive and chronic alcohol intake.