Acute IL-6 treatment increases fatty acid turnover in elderly humans in vivo and in tissue culture in vitro

To determine whether IL-6 increases lipolysis and fat oxidation in patients with type 2 diabetes and/or whether it exerts this effect independently of changes to the hormonal milieu, patients with type 2 diabetes (D) and healthy control subjects (CON) underwent recombinant human (rh)IL-6 infusion for 3 h. Rates of appearance (Ra) and disappearance (Rd) of [U-(13C)]palmitate and [6,6-(2H2)]glucose were determined. rhIL-6 infusion increased (P < 0.05) palmitate Ra and Rd in a similar fashion in both groups. Neither plasma glucose concentration nor glucose Ra/Rd was affected by rhIL-6 infusion in either group, whereas rhIL-6 infusion resulted in a reduction (P < 0.05) in circulating insulin in D. Plasma growth hormone (GH) was increased (P < 0.05) by IL-6 in CON, and cortisol increased (P < 0.05) in response to IL-6 in both groups. To determine whether IL-6 was exerting its effect directly or through activation of these hormones, we performed cell culture experiments. Fully differentiated 3T3-L1 adipocytes were treated with PBS (control) IL-6, or IL-6 plus dexamethasone and GH. IL-6 treatment alone increased (P < 0.05) lipolysis, but this effect was reduced by the addition of dexamethasone and GH such that IL-6 plus dexamethasone and GH had blunted (P < 0.05) lipolysis compared with IL-6 alone. To assess whether IL-6 increases fat oxidation, L6 myotubes were treated with PBS (Control), IL-6, or AICAR, a compound known to increase lipid oxidation. Both IL-6 and AICAR markedly increased (P < 0.05) oxidation of [(14)C]palmitate compared with Control. Acute IL-6 treatment increased fatty acid turnover in D patients as well as healthy CON subjects. Moreover, IL-6 appears to be activating lipolysis independently of elevations in GH and/or cortisol and appears to be a potent catalyst for fat oxidation in muscle cells.     

Antitumor effects of IL-6 on murine liver tumor cells in vivo

IL-6 is a pleiotropic cytokine that is capable of modulating the diverse functions of hepatocytes such as acute phase responses and inflammation in the liver. To learn its antitumor effects in vivo, the cDNA of IL-6 was transfected into murine liver cells, TIB cells. IL-6-transfected TIB cells (TIB73-IL-6 or TIB75-IL-6) produced much higher levels of IL-6 compared with vector-transfected TIB cells (TIB73-vec or TIB75-vec). To investigate the effects of IL-6 on TIB tumor growth in vivo, IL-6-transfected TIB cells or vector-transfected TIB cells were injected subcutaneously into syngeneic mice. Vector-transfected TIB cells grew rapidly 3 weeks after injection, but IL-6-transfected TIB cells did not grow at all for up to 6 weeks. Pathologically, IL-6-transfected TIB cells demonstrated a severe necrosis and apoptotic pattern. Taken together, these results indicate that IL-6 functions as a growth inhibiting factor in vivo, and another biological role of IL-6 in the liver is suggested.     

Endotoxin-induced cytokine gene expression in vivo. III. IL-6 mRNA and serum protein expression and the in vivo hematologic effects of IL-6

Endotoxin (LPS) at sublethal doses injected i.v. into rats was found to induce IL-6 mRNA expression peaking at 1 to 2 h in whole organ RNA preparations of the spleen, liver, lung, bowel, and kidney. IL-6 serum protein levels also peaked at 2 h. TNF and IL-1, generally considered to be among the most rapidly released cytokines, also induced IL-6 expression. IL-6 in turn inhibited TNF and IL-1 expression, suggesting that IL-6 may be part of a negative feedback mechanism in the cytokine cascade. Dexamethasone down-regulated and Corynebacterium parvum up-regulated IL-6 expression, although the possibility cannot be excluded that these immunomodulating factors may in part have exerted their effects indirectly via the up- and down-regulation of TNF and IL-1. IL-6 injected i.v. at a pathophysiologically relevant dose caused a peripheral neutrophilia and mild myeloproliferative effect in the bone marrow.     

The involvement of IL-6 and IL-8 in acute invasive gastroenteritis of children

The involvement of the proinflammatory cytokines, interleukin 8 (IL-8) and 6 (IL-6), was studied during the first 72 h of acute invasive gastroenteritis. Study population included 33 infants and young children aged six months to six years and seven age-matched controls. As a group, patients with acute invasive gastroenteritis had an increased serum level of IL-8 and IL-6 as compared with healthy controls (p < 0.002 and p < 0.001, respectively). Subjects were then divided into two groups based on stool cultures (proven and non-proven bacterial cultures). Patients with bacterial-proven acute invasive gastroenteritis tended to have increased IL-8 serum concentrations (p < 0.07) as compared with those with non-proven bacterial etiologies and IL-6 levels were only detected in subjects with positive bacterial cultures (p < 0.05). When dividing each sub-group into early and late blood drawing with respect to disease onset, no statistical differences were found in each group but subjects with bacterial-proven etiologies had significant higher IL-6 levels as compared with non-proven etiologies at the two time points (p < 0.019 and p < 0.015, respectively).In conclusion, the proinflammatory cytokines, IL-6 and IL-8, are involved in acute invasive gastroenteritis. The difference in IL-6, and to a lesser degree IL-8, between proven and non-proven bacterial etiologies, needs further investigation.     

Cardiac role of frog ANF: negative inotropism and binding sites in Rana esculenta

To elucidate the role of atrial natriuretic peptides (NPs) in the amphibian heart, the myotropic effects and the cardiac distribution of frog atrial natriuretic factor (fANF) have been studied in Rana esculenta. Spontaneously, beating in vitro isolated working heart preparations were treated with increased concentrations (10(-11)-10(-8) M) of fANF-(1-24). The peptide at 10(-9) and 10(-8) M significantly reduced heart rate (HR) and, on the electrically paced preparations, decreased cardiac output (CO), stroke volume (SV) and work. Such negative inotropism was abolished by pretreatment with the pertussis toxin or by blocking the particulate guanylate cyclase (GC) with anantin while it was independent both from the functional impairment of the endocardium-endothelium by Triton X-100 and the inhibition of the soluble guanylate cyclase by 1 H-(1,2,4,) oxadiazolo-(4,3-a) quinoxalin-1-one (ODQ). By autoradiography, two classes of high and low affinity NPs binding sites were detected in the ventricular endocardium and myocardium and in the bulbus arteriosus. The analysis of displacement binding data using the radioligand [125I]-rat atrial natriuretic peptide [125I-rANP-(1-28)], its cold counterpart and the fANF-(1-24) showed that in the ventricular myocardium, the low affinity NPs sites bound both the heterologous and the homologous ligands at a concentration close to that responsible for the negative inotropism and chronotropism.     

Stat6 regulation of in vivo IL-4 responses

Although in vitro development of a Th2 response from naive CD4+ T cells is Stat6 dependent, mice immunized with a goat Ab to mouse IgD have been reported to produce a normal primary IL-4 response in Stat6-deficient mice. Experiments have now been performed with mice immunized with more conventional Ags or inoculated with nematode parasites to account for this apparent discrepancy. The ability of an immunogen to induce a primary in vivo IL-4 response in Stat6-deficient mice was found to vary directly with its ability to induce a strong type 2 cytokine-biased response in normal mice. Even immunogens, however, that induce strong primary IL-4 responses in Stat6-deficient mice induce poor memory IL-4 responses in these mice. Consistent with this, Stat6-deficient CD4+ T cells make relatively normal IL-4 responses when stimulated in vitro for 3 days with anti-CD3 and anti-CD28, but poor IL-4 responses if they are later restimulated with anti-CD3. Thus, Stat6 signaling enhances primary IL-4 responses that are made as part of a type 0 cytokine response (mixed type 1 and type 2) and is required for normal development or survival of Th2 memory cells.     

Myeloarchitectonics of the vagus nerve in man

In serial electively stained transversal sections of the vagus nerve trunk taken at the levels beginning from its exit out of the brain, up to terminal branches in the abdominal cavity (10 corpses of mature persons) myelin fibers of three classes have been counted. Along the course of the nerve trunk in the craniocaudal direction the total number of the myelin fibers decreases. Only about 10% of the initial amount of the myelin conductors revealed at the level of the intracranial part of the vagus nerve get into the abdominal cavity. Simultaneously, the ratio of the myelin fibers belonging to different classes changes: the part of the fine conductors increases, and that of the fibers having middle and large diameters decreases. The most important in the dynamics of the whole amount of myelin fibers and in the number of the conductors belonging to different classes at all the levels of the nerve trunk is the getting off the organs' branches with various functional specialization.     

Protective potential of IL-6 against trimethyltin-induced neurotoxicity in vivo

We investigated the role of cytokines in trimethyltin (TMT)-induced convulsive neurotoxicity. Evaluation of TNF-α, interferon-γ, and interleukin (IL)-6 knockout (-/-) mice showed that the IL-6(-/-) mice had the greatest susceptibility to TMT-induced seizures. In both wild-type and IL-6(-/-) mice, TMT treatment increased glutathione oxidation, lipid peroxidation, protein oxidation, and levels of reactive oxygen species in the hippocampus. These effects were more pronounced in the IL-6(-/-) mice than in wild-type controls. In addition, the ability of TMT to induce nuclear translocation of Nrf2 and upregulation of heme oxygenase-1 and γ-glutamylcysteine ligase was significantly decreased in IL-6(-/-) mice. Treatment of IL-6(-/-) mice with recombinant IL-6 protein (rIL-6) restored these effects of TMT. Treatment with rIL-6 also significantly attenuated the TMT-induced inhibition of phosphoinositol 3-kinase (PI3K)/Akt signaling, thereby increasing phosphorylation of Bad (Bcl-xL/Bcl-2-associated death promoter protein), expression of Bcl-xL and Bcl-2, and the interaction between p-Bad and 14-3-3 protein and decreasing Bax expression and caspase-3 cleavage. Furthermore, in IL-6(-/-) mice, rIL-6 provided significant protection against TMT-induced neuronal degeneration; this effect of rIL-6 was counteracted by the PI3K inhibitor LY294002. These results suggest that activation of Nrf2-dependent glutathione homeostasis and PI3K/Akt signaling is required for the neuroprotective effects of IL-6 against TMT.     

Role of the vagus nerve in mechanisms of the modulation of afferent duodenal effects]

The electrostimulation of vagal nerves, the effect of naloxone and atropine on duodenal afferentation by registering evoked potential (EP) at cortex on direct electrostimulation of duodenum have been studied in acute experiments on cats. It has been established that the stimulation of afferent portion of vagal nerves causes the effect of deprivation of EP, whereas the stimulation with certain intensity of efferent portion of vagal nerves intensifies the duodenal afferentation. The effect of afferentation easeness (relief) has been blocked by the application of naloxone 10-20 microgram on duodenal bulbus, but not on it's i. v. injection and without effect on local application of atropine. It is concluded that the role of vagal nerves on the modulation of duodenal nociception is due to the activation of opiate terminals of the efferent vagal nerve portions.     

Acute haemodynamic effects and tissue distribution of acebutolol in normotensive and spontaneously hypertensive rats

Acute i.v. administration of 15 mg/kg acebutolol in normotensive (WKY), Okamoto (SHR) and Okamoto stroke-prone (SHR-SP) awake rats resulted in weak effects on blood pressure and in bradycardia more marked in SHR-SP. Thirty minutes after i.v. administration, lung and renal uptake of [14C]acebutolol was reduced in SHR compared to other rats. Muscle uptake was higher in SHR and blood concentration was higher in SHR-SP. Brain levels were low and similar in all rats. Plasma protein binding was identical in all rats. These results are discussed according to the characteristics of the three strains studied.     

Electrical stimulation of afferent vagus nerve induces IL-1beta expression in the brain and activates HPA axis

Possible roles of the afferent vagus nerve in regulation of interleukin (IL)-1beta expression in the brain and hypothalamic-pituitary-adrenal (HPA) axis were examined in anesthetized rats. Levels of IL-1beta mRNA and protein in the brain were measured by comparative RT-PCR and ELISA. Direct electrical stimulation of the central end of the vagus nerve was performed continuously for 2 h. The afferent stimulation of the vagus nerve induced increases in the expression of mRNA and protein levels of IL-1beta in the hypothalamus and the hippocampus. Furthermore, expression of corticotropin-releasing factor mRNA was increased in the hypothalamus 2 h after vagal stimulation. Plasma levels of ACTH and corticosterone were also increased by this stimulation. The present results indicate that activation of the afferent vagus nerves itself can induce production of IL-1beta in the brain and activate the HPA axis. Therefore, the afferent vagus nerve may play an important role in transmitting peripheral signals to the brain in the infection and inflammation.     

The role of the vagus nerve in depression

The etiopathogenesis of depression is a highly complex process characterized by several neurobiological alterations including decreased monoamine neurotransmission in the brain, dysregulated hypothalamic-pituitary-adrenal axis activity, decreased neuronal plasticity, and chronic inflammation in the brain and peripheral tissues. Experimental and clinical studies indicate that the vagus nerve may influence these processes. The importance of the vagus nerve in the etiopathogenesis of depression is further supported by its involvement in the induction of sickness behavior, as well as by clinical studies confirming a beneficial effect of vagus nerve stimulation in depressed patients. The aim of this article is to describe current knowledge of afferent and efferent vagal pathways role in the development and progression of depression.     

The effects of trifluoperazine on fast and slow axonal transport in the rabbit vagus nerve

The effects of trifluoperazine (TFP) on fast and slow axonal transport (AXT) of labeled proteins were examined in the rabbit vagus nerve. Cuffs soaked in a 10 mM, but not 0.1 mM or 1 mM, concentration of TFP applied locally around the vagus nerve in vivo blocked both fast and slow AXT, as measured by the accumulation of 3H-labeled proteins. In vitro, fast AXT was affected by 0.1 mM TFP. The TFP cuff treatment caused a reduction in the number of axonal microtubules (MT) whereas cuffs soaked in saline had no effect. The levels of ATP, ADP, and AMP were not significantly lowered by the TFP treatment. The results suggest that both fast and slow AXT are sensitive to TFP treatment, and that the axonal MT-system may be the main target of the drug.     

The involvement of TNF,IL-1 and IL-6 in the immune response to protozoan parasites

One early reaction of the host to infection with protozoan parasites is the secretion of an array of potent cytokines including tumor necrosis factor (TNF), interleukin 1 (IL-1) and IL-6. The combined action of these cytokines causes fever, leukocytosis and the production of acute phase proteins such as C-reactive protein (CRP). These early responses contribute significantly to the outcome of infection by influencing the course of infection directly and by regulating the specific immune response to the parasite.     

Acute and long-term effects of IL-6 on cultured dorsal root ganglion neurones from adult rat

IL-6 contributes to pain and hyperalgesia in inflamed tissue. We have investigated short- and long-term effects of IL-6 on dorsal root ganglion (DRG) neurones. Glycoprotein 130-like immunoreactivity (the signal transduction receptor subunit) was found in almost all neurones in DRG sections and in cultured DRG neurones from adult rat. In calcium-imaging studies bath application of IL-6 caused an increase of intracellular calcium in about one-third of the DRG neurones suggesting functional IL-6 receptors in a proportion of neurones. Long-term but not short-term exposure of DRG neurones to IL-6 in vitro significantly enhanced the proportion of DRG neurones expressing neurokinin 1 receptor-like immunoreactivity from 10% to up to 40%. This up-regulation was dependent on the activation of mitogen-activated protein kinase kinase (MEK) in the neurones, suggesting that the mitogen-activated protein kinase (MAPK) pathway is important for this effects of IL-6. Calcium-imaging studies demonstrated that previous exposure of DRG neurones to IL-6 enhanced the proportion of neurones that exhibit a substance P-induced rise in intracellular calcium. These data show that IL-6 has short- and long-term effects on a proportion of DRG neurones. These effects are likely to contribute to pro-nociceptive effects of IL-6.     

Chronic interleukin-6 (IL-6) treatment increased IL-6 secretion and induced insulin resistance in adipocyte: prevention by rosiglitazone

IL-6 has emerged as an important cytokine upregulated in states of insulin resistance such as type 2 diabetes. We evaluated the chronic effect of IL-6 on insulin signaling in 3T3-F442A and 3T3-L1 adipocytes. First, cells responded to a chronic treatment with IL-6 by initiating an autoactivation process that increased IL-6 secretion. Second, IL-6-treated adipocytes showed a decreased protein expression of IR-beta subunit and IRS-1 but also an inhibition of the insulin-induced activation of IR-beta, Akt/PKB, and ERK1/2. Moreover, IL-6 suppressed the insulin-induced lipogenesis and glucose transport consistent with a diminished expression of GLUT4. IL-6-treated adipocytes failed to maintain their adipocyte phenotype as shown by the downregulation of the adipogenic markers FAS, GAPDH, aP2, PPAR-gamma, and C/EBP-alpha. IL-6 also induced the expression of SOCS-3, a potential inhibitor of insulin signaling. Finally, the effects of IL-6 could be prevented by rosiglitazone, an insulin-sensitizing agent. Thus, IL-6 may play an important role in the set-up of insulin resistance in adipose cell.     

Bronchial vasodilator pathways in the vagus nerve of dogs

Bronchialvasodilation in dogs is mediated largely by vagal pathways. To examinethe relative contribution of cholinergic and noncholinergicparasympathetic pathways and of sensory axon reflexes to vagalbronchial vasodilation, we electrically stimulated the peripheral vagusnerve in 10 chloralose-anesthetized dogs and measured bronchial arteryflow. Moderate-intensity electrical stimulation (which did not activateC-fiber axons) caused a rapid voltage- and frequency-dependentvasodilation. After atropine, vasodilation was slower in onset andreduced at all voltages and frequencies: bronchial vascular conductanceincreased by 9.0 ± 1.5 (SE)ml · min¹ · 100 mmHg¹ during stimulationbefore atropine and 5.5 ± 1.4 ml · min¹ · 100 mmHg¹ after(P < 0.02). High-intensitystimulation (sufficient to recruit C fibers) was not studied beforeatropine because of the resulting cardiac arrest. After atropine,high-intensity stimulation increased conductance by 12.0 ± 2.5 ml · min¹ · 100 mmHg¹. Subsequent blockadeof ganglionic transmission, with arterial blood pressure maintained bya pressure reservoir, abolished the response to moderate-intensitystimulation and reduced the increase to high-intensity stimulation by82 ± 5% (P < 0.01). In 13 other dogs, we measured vasoactive intestinalpeptide-like immunoreactivity in venous blood draining from thebronchial veins. High-intensity vagal stimulationincreased vasoactive intestinal peptide concentration from 5.7 ± 1.8 to 18.4 ± 4.1 fmol/ml (P = 0.001). The results suggest that in dogs cholinergic and noncholinergicparasympathetic pathways play the major role in vagal bronchial vasodilation.