Involvement of brain cytokines in zymosan-induced febrile response

2014 ◽  
Vol 116 (9) ◽  
pp. 1220-1229 ◽  
Author(s):  
Amanda L. Bastos-Pereira ◽  
Daniel Fraga ◽  
Daniela Ott ◽  
Björn Simm ◽  
Jolanta Murgott ◽  
...  
Keyword(s):  
Time Course ◽  
Calcium Concentration ◽  
Febrile Response ◽  
Tnf Α ◽  
Heat Conservation ◽  
The Central Nervous System ◽  
Factor Α ◽  
The Brain ◽  
Circulating Levels ◽  
Necrosis Factor

This study compared the involvement of interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α) within the central nervous system (CNS) in the febrile response induced by zymosan (zym) and lipopolysaccharide (LPS). In addition, we investigated whether zym could activate important regions related to fever; namely, the vascular organ of the laminae terminalis (OVLT) and the median preoptic nucleus (MnPO). Intraperitoneal injection of zym (1, 3, and 10 mg/kg) induced a dose-related increase in core temperature. Zym (3 mg/kg) also reduced tail skin temperature, suggesting the activation of heat conservation mechanisms, as expected, during fever. LPS increased plasma levels of TNF-α measured at 1 h, IL-1β measured at 2 h, and IL-6 measured at 3 h after injection. Zym increased circulating levels of IL-6 but not those of TNF-α or IL-1β at the same time points. In addition, an intracerebroventricular injection of antibodies against TNF-α (2.5 μg) and IL-6 (10 μg) or the IL-1 receptor antagonist (160 ng) reduced the febrile response induced by zym and LPS. Zym (100 μg/ml) also increased intracellular calcium concentration in the OVLT and MnPO from rat primary neuroglial cultures and increased release of TNF-α and IL-6 into the supernatants of these cultures. Together, these results suggest that TNF-α, IL-1β, and IL-6 within the CNS participate in the febrile response induced by zym. However, the time course of release of these cytokines may be different from that of LPS. In addition, zym can directly activate the brain areas related to fever.

Induction of endogenous tumor necrosis factor-α: suppression of centrally stimulated gastric motility

1999 ◽  
Vol 276 (1) ◽  
pp. R59-R68 ◽  
Author(s):  
Gerlinda E. Hermann ◽  
C. Amy Tovar ◽  
Richard C. Rogers
Keyword(s):  
Tumor Necrosis Factor ◽  
Gastric Motility ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Gastric Stasis ◽  
Intravenous Injections ◽  
Tnf Α ◽  
Factor Α ◽  
Circulating Levels ◽  
Necrosis Factor

Gastric stasis is frequently seen in conjunction with critical infectious illness, chronic inflammatory disorders, radiation sickness, and carcinogenesis. These conditions are associated with elevated circulating levels of the cytokine tumor necrosis factor-α (TNF-α). The present studies examined the relationship between endogenously produced TNF-α and the central neural mechanisms that augment gastric motility. Systemic lipopolysaccharide (LPS) was employed to induce TNF-α production in thiobutabarbital-anesthetized rats. Sixty minutes after intravenous LPS injection, gastric motility could not be stimulated by a potent centrally acting gastrokinetic stimulant, thyrotropin-releasing hormone (TRH). This failure to elicit gastric motility via central mechanisms coincided with high circulating levels of TNF-α. However, intravenous injections of bethanecol, a peripherally acting cholinergic agonist with direct gastrokinetic effects, were still able to elicit normal increases in gastric motility in the presence of TNF-α and LPS. Therefore, the inability to stimulate gastric motility via central TRH could not be attributed to the direct inhibitory effects of either LPS or TNF-α on the stomach. If the production of endogenous TNF-α was suppressed via the use of urethan as the anesthetic agent, then intravenous injections of LPS were no longer effective in suppressing gastric motility. Thus these effects on gastric motility are not directly attributable to LPS nor are they due to direct effects on the gastric smooth muscle. Our previous study demonstrated that microinjection of femtomole quantities of TNF-α in the brain stem dorsal vagal complex (DVC) can modulate gastric motility. This central TNF-α effect on gastric motility was dose dependent and required an intact vagal efferent pathway. The results from these two studies suggest that systemically produced TNF-α may gain access to the DVC to modulate gastric function.

scholarly journals Direct Evidence for Central Proinflammatory Mechanisms in Rats with Experimental Acute Liver Failure: Protective Effect of Hypothermia

2009 ◽  
Vol 29 (5) ◽  
pp. 944-952 ◽  
Author(s):  
Wenlei Jiang ◽  
Paul Desjardins ◽  
Roger F Butterworth
Keyword(s):  
Liver Failure ◽  
Acute Liver Failure ◽  
Brain Edema ◽  
Proinflammatory Cytokines ◽  
Direct Evidence ◽  
Mild Hypothermia ◽  
Tnf Α ◽  
Factor Α ◽  
The Brain ◽  
Necrosis Factor

It has been proposed that proinflammatory mechanisms are involved in the pathogenesis of brain edema in acute liver failure (ALF). The aim of this study was to assess the contribution of cerebral inflammation to the neurologic complications of ALF and to assess the antiinflammatory effect of mild hypothermia. Upregulation of CD11b/c immunoreactivity, consistent with microglial activation, was observed in the brains of ALF rats at coma stages of encephalopathy. Interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) mRNAs were increased two to threefold in the brains of ALF rats compared with that in sham-operated controls. The magnitude of increased expression of proinflammatory cytokines in the brain was correlated with the progression of encephalopathy and the onset of brain edema. Significant increases in IL-1β, IL-6, and TNF-α levels were also found in the sera and cerebrospinal fluid (CSF) of these animals. Mild hypothermia delayed the onset of encephalopathy, prevented brain edema, and concomitantly attenuated plasma, brain, and CSF proinflammatory cytokines. These results show that experimental ALF leads to increases in brain production of proinflammatory cytokines, and afford the first direct evidence that central inflammatory mechanisms play a role in the pathogenesis of the cerebral complications of ALF. Antiinflammatory agents could be beneficial in the management of these complications.

Diversity and Regulation of Astrocyte Neurotoxicity in Alzheimer's Disease

2021 ◽  
Vol 18 ◽  
Author(s):  
Sadayuki Hashioka ◽  
James G. McLarnon ◽  
Andis Klegeris
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Nuclear Imaging ◽  
Resonance Spectroscopy ◽  
Tnf Α ◽  
Factor Α ◽  
The Brain ◽  
Harmful Effects ◽  
Necrosis Factor

: Astrocytes contribute to brain development and homeostasis and support diverse functions of neurons. These cells also respond to the pathological processes in Alzheimer’s disease (AD). There is still considerable debate concerning the overall contribution of astrocytes to AD pathogenesis since both the protective and harmful effects of these cells on neuronal survival have been documented. This review focuses exclusively on the neurotoxic potential of astrocytes while acknowledging that these cells can contribute to neurodegeneration through other mechanisms, for example, by lowered neurotrophic support. We identify reactive oxygen and nitrogen species, tumor necrosis factor α (TNF-α), glutamate, and matrix metalloproteinase (MMP)-9 as molecules that can be directly toxic to neurons and are released by reactive astrocytes. There is also considerable evidence suggesting their involvement in AD pathogenesis. We further discuss the signaling molecules that trigger the neurotoxic response of astrocytes with a focus on human cells. We also highlight microglia, the immune cells of the brain, as critical regulators of astrocyte neurotoxicity. Nuclear imaging and magnetic resonance spectroscopy (MRS) could be used to confirm the contribution of astrocyte neurotoxicity to AD progression. The molecular mechanisms discussed in this review could be targeted in the development of novel therapies for AD.

Effect of Blockade of Tumor Necrosis Factor-α with Etanercept on Surgical Wound Healing in SWISS-OF1 Mice

2009 ◽  
Vol 36 (10) ◽  
pp. 2144-2148 ◽  
Author(s):  
ESTIBALIZ IGLESIAS ◽  
FRANCISCO O’VALLE ◽  
JUAN SALVATIERRA ◽  
JOSE ANEIROS-FERNÁNDEZ ◽  
JESUS CANTERO-HINOJOSA ◽  
...  
Keyword(s):  
Wound Healing ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Time Course ◽  
Tumor Necrosis Factor Α ◽  
Healing Time ◽  
Surgical Wound ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

Objective.To assess whether blockade of tumor necrosis factor-α (TNF-α) influences surgical wound healing in a normal mouse experimental model.Methods.Wound healing time course and degree of surgical wound collagenization were measured by morphological techniques and digital image analysis in 80 male SWISS-OF1 mice (40 received subcutaneous etanercept at a dose of 0.1 mg/25g/ at −7, 0, 7, and 14 days).Results.No significant differences were observed between treated and untreated animals in wound healing, re-epithelialization, or formation of inflammatory infiltrate or granulation tissue at days 7, 15, or 20 after surgery. At 20 days, the collagen area was larger in treated versus untreated mice (109029 ± 28489 μm2 vs 79305 ± 19798 μm2, p = 0.026, Mann-Whitney U test).Conclusion.Surgical wounds showed a higher degree of collagenization at 20 days in etanercept-treated versus untreated mice, with no differences in the time course of wound healing. These data suggest that biological therapies to block TNF-α do not affect wound healing and do not need to be suspended during the perioperative period.

scholarly journals IL-1 is a mediator of increases in slow-wave sleep induced by CRH receptor blockade

2000 ◽  
Vol 279 (3) ◽  
pp. R793-R802 ◽  
Author(s):  
Fang-Chia Chang ◽  
Mark R. Opp
Keyword(s):  
Hpa Axis ◽  
Slow Wave ◽  
Tumor Necrosis ◽  
Slow Wave Sleep ◽  
Central Administration ◽  
Regulatory Systems ◽  
The Central Nervous System ◽  
Factor Α ◽  
The Brain ◽  
Necrosis Factor

We hypothesize that corticotropin-releasing hormone (CRH), a regulator of the hypothalamic-pituitary-adrenal (HPA) axis, is involved in sleep-wake regulation on the basis of observations that the CRH receptor antagonist astressin, after a delay of several hours, reduces waking and increases slow-wave sleep (SWS) in rats. This delay suggests a cascade of events that begins with the HPA axis and culminates with actions on sleep regulatory systems in the central nervous system. One candidate mediator in the brain for these actions is interleukin (IL)-1. IL-1 promotes sleep, and glucocorticoids inhibit IL-1 synthesis. In this study, central administration of 12.5 μg astressin into rats before dark onset reduced corticosterone 4 h after injection and increased mRNA expression for IL-1α and IL-1β but not for IL-6 or tumor necrosis factor-α in the brain 6 h after injection. To determine directly whether IL-1 is involved in astressin-induced alterations in sleep-wake behavior, we then pretreated rats with 20 μg anti-IL-1β antibodies before injecting astressin. The increase in SWS and the reduction in waking that occur after astressin are abolished when animals are pretreated with anti-IL-1β. These data indicate that IL-1 is a mediator of astressin-induced alterations in sleep-wake behavior.

Mineralocorticoids act centrally to regulate blood-borne tumor necrosis factor-α in normal rats

2003 ◽  
Vol 285 (6) ◽  
pp. R1402-R1409 ◽  
Author(s):  
Joseph Francis ◽  
Terry Beltz ◽  
Alan Kim Johnson ◽  
Robert B. Felder
Keyword(s):  
Mineralocorticoid Receptor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Progressive Increase ◽  
Peripheral Tissues ◽  
Intracerebroventricular Infusion ◽  
Tnf Α ◽  
Factor Α ◽  
Circulating Levels ◽  
Necrosis Factor

Excessive mineralocorticoid receptor (MR) stimulation induces neurohumoral excitation and cardiac and vascular fibrosis. In heart failure (HF) rats, with excessive neurohumoral drive, central infusion of the MR antagonist spironolactone (SL) decreases blood-borne TNF-α. This study aimed to determine whether DOCA, a precursor of aldosterone, acts centrally to stimulate TNF-α production in normal rats. DOCA (5 mg sc daily for 8 days) induced a progressive increase in TNF-α beginning on day 3 and increased tissue TNF-α in hypothalamus, pituitary, and heart but not in other brain and peripheral tissues harvested on day 9. A continuous intracerebroventricular infusion of SL (100 ng/h) blocked the plasma TNF-α response. Oral SL (1 mg/kg) blocked the plasma and tissue TNF-α responses. Thus DOCA increases TNF-α in brain, heart, and blood in normal rats. Activation of brain MR appears to account for the increase in plasma TNF-α. These findings have important implications for the understanding of pathophysiological states (e.g., HF, hypertension) characterized by high circulating levels of aldosterone.

IL-6 is essential in TNF-α-induced fever

1998 ◽  
Vol 275 (6) ◽  
pp. R2028-R2034 ◽  
Author(s):  
Anna K. Sundgren-Andersson ◽  
Pernilla Östlund ◽  
Tamas Bartfai
Keyword(s):  
Tumor Necrosis ◽  
Prostaglandin E ◽  
High Dose ◽  
Central Administration ◽  
Wild Type ◽  
Febrile Response ◽  
Tnf Α ◽  
Factor Α ◽  
Deficient Mice ◽  
Necrosis Factor

Tumor necrosis factor-α (TNF-α) is a pleiotropic cytokine that orchestrates an array of local and systemic effects. For instance, acute exposure to a high dose of TNF-α results in septic shock and fever. We have used interleukin-1β (IL-1β)- and interleukin-6 (IL-6)-deficient mice, along with their wild-type equivalents, to define a role for TNF-α in fever. Briefly, the mice produced prostaglandin E2-dependent fevers in response to recombinant murine TNF-α (rmTNF-α). Furthermore, rmTNF-α (12 μg/mouse ip) triggered a febrile response in IL-1β-deficient mice as well as in their corresponding wild-type controls. In contrast, the IL-6-deficient mice were resistant to rmTNF-α (4.5 μg/mouse ip), although their wild-type counterparts readily mounted a fever. In the IL-6-deficient mice, moreover, the febrile response to rmTNF-α could be restored by a central administration of rat recombinant IL-6 (500 ng/mouse icv). We thus conclude that TNF-α can trigger fever independent of IL-1β but dependent on IL-6. We also suggest that central, rather than peripheral, IL-6 (plasma IL-6 was measured 2 h after pyrogenic challenge) is essential in TNF-α-induced fever.

Tumor necrosis factor-α (TNF-α) increases both in the brain and in the cerebrospinal fluid from parkinsonian patients

1994 ◽  
Vol 165 (1-2) ◽  
pp. 208-210 ◽  
Author(s):  
Makio Mogi ◽  
Minoru Harada ◽  
Peter Riederer ◽  
Hirotaro Narabayashi ◽  
Keisuke Fujita ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Tnf Α ◽  
Factor Α ◽  
The Brain ◽  
Necrosis Factor

scholarly journals Increased Cytokine Release from Peripheral Blood Cells after Acute Stroke

1999 ◽  
Vol 19 (9) ◽  
pp. 1004-1009 ◽  
Author(s):  
Carlo Ferrarese ◽  
Paolo Mascarucci ◽  
Chiara Zoia ◽  
Rosella Cavarretta ◽  
Maura Frigo ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Blood Cells ◽  
Time Course ◽  
Serum Levels ◽  
Peripheral Blood Cells ◽  
Stroke Patients ◽  
Tnf Α ◽  
The Brain ◽  
Necrosis Factor ◽  
Time Point

Cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-α can play pathogenetic or protective roles in stroke. They are increased in the brain after experimental ischemia and in the CSF of patients with stroke. However, their presence in the periphery is still controversial. To determine the source and time-course of cytokines in blood of stroke patients, IL-6 and TNF-α release from blood cells and serum levels were determined in 40 patients on days 1 through 2, 4, 10, 30, and 90 after stroke. Twenty healthy age-matched volunteers were used as controls. IL-6 and TNF-α release from stimulated blood cells was increased in stroke patients, compared to controls. A peak response (+224%) was observed at day 4 for IL-6, while TNF-α release was largely and significantly increased (about three-fold compared to controls) from day 1 to 2 until day 90 after stroke. The increase in IL-6 release was significantly higher in ischemic, compared to hemorragic strokes, at days 1 and 4. Circulating IL-6 was increased at each time point. The ischemic processes in the CNS induces a long-lasting activation of IL-6 and TNF-α production in peripheral blood cells, which are a major source of serum cytokines after stroke.

Attenuated febrile response to lipopolysaccharide in rats with biliary obstruction

2000 ◽  
Vol 279 (1) ◽  
pp. G172-G177 ◽  
Author(s):  
L. K. McCullough ◽  
Y. Takahashi ◽  
T. Le ◽  
Q. J. Pittman ◽  
M. G. Swain
Keyword(s):  
Serum Levels ◽  
Sham Operation ◽  
Sprague Dawley ◽  
Febrile Response ◽  
Perioperative Morbidity ◽  
Sprague Dawley Rats ◽  
Tnf Α ◽  
Factor Α ◽  
Generation Male ◽  
Necrosis Factor

Patients with biliary tract obstruction have unexplained, inordinately high rates of perioperative morbidity and mortality, whereas cholestatic animals display abnormal hypothalamic responses to pyrogenic stimuli. We asked if obstructive cholestasis was associated with abnormal fever generation. Male Sprague-Dawley rats (250 g) underwent laparotomy for implantation of thermistors and either bile duct resection (BDR) or sham operation. After recovery, temperatures were recorded by telemetry and conscious, unrestrained rats in each group were injected intraperitoneally with either interleukin-1β (IL-1β;1 μg/kg) or Escherichia colilipopolysaccharide (LPS; 50 μg/kg). Baseline temperatures in both groups were similar. Febrile responses after IL-1β injection in BDR and sham groups were not significantly different. However, in response to LPS injection, BDR rats showed an initial hypothermia with a subsequently attenuated febrile response. Administration of anti-tumor necrosis factor-α (TNF-α) antibody 2 h before LPS injection blocked the LPS-induced hypothermia seen in BDR animals. However, serum levels of TNF-α were not significantly different between sham and BDR animals after LPS injection at any time point measured (0, 1.5, and 3 h).

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