Progesterone modulates extracellular heat-shock proteins and interlukin-1ß in human choriodecidual after Escherichia coli infection.

INTRODUCTION: Chorioamnionitis is an adverse condition in human pregnancy caused by many bacterial pathogens including Escherichia coli (E. coli); which has been associated with higher risk of preterm birth. We recently reported that human maternal decidua (MDec) tissue responds to E. coli infection by secreting extracellular heat-shock proteins (eHsp)-60, -70 and interlukin-1ß (IL-1ß). Previous studies have shown that progesterone (P4) regulates the immune response, but it is unknown whether P4 inhibits the secretion of eHsp. The aim of this investigation was to determine the role of P4 on the secretion of eHsp-27, -60, -70 and IL-1ß in MDec after 3, 6, and 24 h of E. coli infection. METHODS: Nine human feto-maternal interface (HFMi) tissues were included and mounted in the Transwell culture system. Only the maternal decidua (MDec) was stimulated for 3, 6 and 24 h with E. coli alone or in combination with progesterone and RU486. After each treatment, the HFMi tissue was recovered to determine histological changes and the culture medium recovered to evaluate the levels of eHsp-27, -60, -70 and IL-1ß by ELISA and mRNA expression by RT-PCR. RESULTS: No structural changes were observed in the HFMi tissue treated with P4 and RU486. However, stimulation with E. coli produces diffuse inflammation and ischemic necrosis. E. coli induced infection decreases, in time- and dose-dependent manner, eHsp-27 and increases eHsp-60, eHsp-70 and IL-1ß levels. In contrast, incubation of HFMi tissue with E. coli + P4 reversed eHsp and IL-1ß secretion levels relative to E. coli stimulation group but not relative to the control group. The same profile was observed on the expression of eHsp-27 and eHsp-60. DISCUSSION: we found that progesterone modulates the anti-inflammatory (eHsp-27) and pro-inflammatory (eHsp-60 and eHsp-70) levels of eHsp induced by E. coli infection in human choriodecidual tissue. eHsp-60 and eHsp-70 levels were not completely reversed; maintaining the secretion of IL-1ß, which has been associated with adverse events during pregnancy.

Current Medical Treatment for Alcohol-Associated Liver Disease.

Alcohol-associated liver disease is one of the main causes of chronic liver disease. It comprises a clinical-histologic spectrum of presentations, from steatosis, steatohepatitis, to different degrees of fibrosis, including cirrhosis and severe necroinflammatory disease, called alcohol-associated hepatitis. In this focused update, we aim to present specific therapeutic interventions and strategies for the management of alcohol-associated liver disease. Current evidence for management in all spectra of manifestations is derived from general chronic liver disease recommendations, but with a higher emphasis on abstinence and nutritional support. Abstinence should comprise the treatment of alcohol use disorder as well as withdrawal syndrome. Nutritional assessment should also consider the presence of sarcopenia and its clinical manifestation, frailty. The degree of compensation of the disease should be evaluated, and complications, actively sought. The most severe acute form of this disease is alcohol-associated hepatitis, which has high mortality and morbidity. Current treatment is based on corticosteroids that act by reducing immune activation and blocking cytotoxicity and inflammation pathways. Other aspects of treatment include preventing and treating hepatorenal syndrome as well as preventing infections although there is no clear evidence as to the benefit of probiotics and antibiotics in prophylaxis. Novel therapies for alcohol-associated hepatitis include metadoxine, interleukin-22 analogs, and interleukin-1-beta antagonists. Finally, granulocyte colony-stimulating factor, microbiota transplantation, and gut-liver axis modulation have shown promising results. We also discuss palliative care in advanced alcohol-associated liver disease.

Neuroinflammatory responses following zinc or branched-chain amino acids supplementation in obese rats.

The excessive production of pro-inflammatory mediators, characteristic of obesity, leads to neuroinflammation. Zinc (Zn) and the branched-chain amino acids (BCAA) are supplements known for their immunomodulatory properties. Our goal was to evaluate if Zn or BCAA supplementation can affect long-term recognition memory and neuroinflammatory parameters of obese rats after a high-fat diet (HFD). Three-month-old Wistar rats were divided into six groups: Standard diet (SD) + vehicle; SD + Zn; SD + BCAA; High-fat diet (HFD) + vehicle; HFD + Zn; and HFD + BCAA. Diets were administrated for 19 weeks, Zn (1,2 mg/kg/day) or BCAA (750 mg/kg/day) supplementation was conducted in the last 4 weeks. Long-term recognition memory was evaluated by the novel object recognition test. IL-1ß immunoreactivity in the cortex and hippocampus, and IL-6 levels in the cortex tissue were assessed. Astrogliosis were evaluated through GFAP + cell count and morphological analysis (Sholl Method). Zn supplementation improved object recognition memory in HFD-fed rats, which was not observed following BCAA supplementation. The levels of IL-6 in the cerebral cortex were higher after HFD, which was not diminished after neither supplementation. Obesity also led to increased IL-1ß immunoreactivity in the cerebral cortex and hippocampus, which was reduced by Zn. BCAA supplementation also diminished IL-1ß immunoreactivity, but only in the hippocampus. We also showed that astrocyte reactivity caused by HFD is area-dependent, being the cerebral cortex more susceptible to the diet. Even though BCAA and Zn can affect IL-1ß immunoreactivity and astrocyte morphology, only Zn improved memory. Future studies are needed to clarify the pathways by which Zn improves cognition in obesity.

Curcumin attenuates LPS-induced sickness behavior and fever in rats by modulating Nrf2 activity.

Lipopolysaccharide (LPS) is a potent inducer of inflammation, triggering behavioral changes and fever. The present study aimed to evaluate whether pretreatment with curcumin prevents the behavioral changes and fever induced by LPS through the modulation of nuclear factor-erythroid 2 related factor 2 (Nrf2). Male Wistar rats received either vehicle or LPS and after 2 h, the behavioral responses were assessed through open field test (OFT), social interaction test, forced swim test (FST), and food intake assessment. The febrile response was assessed by telemetry after vehicle or LPS injection to evaluate the effect of curcumin on the thermoregulatory response during the immunological challenge. The pretreatment with curcumin at doses of 50 and 100 mg/kg prevented the reduction of distance traveled on OFT, increased the immobility time of FST, impaired social withdrawal, decreased food intake, and induced fever. In addition, at these doses, it was possible to observe a significant decrease in the plasma levels of cytokines and an increase in Nrf2 translocation to the cell nucleus during the immunological challenge. Our data provide further evidence of curcumin's ability to prevent LPS-induced sickness behavior and fever possibly by a mechanism related to the modulation of Nrf2 translocation.

Involvement of Inflammasome Components in Kidney Disease.

Inflammasomes are multiprotein complexes with an important role in the innate immune response. Canonical activation of inflammasomes results in caspase-1 activation and maturation of cytokines interleukin-1ß and -18. These cytokines can elicit their effects through receptor activation, both locally within a certain tissue and systemically. Animal models of kidney diseases have shown inflammasome involvement in inflammation, pyroptosis and fibrosis. In particular, the inflammasome component nucleotide-binding domain-like receptor family pyrin domain containing 3 (NLRP3) and related canonical mechanisms have been investigated. However, it has become increasingly clear that other inflammasome components are also of importance in kidney disease. Moreover, it is becoming obvious that the range of molecular interaction partners of inflammasome components in kidney diseases is wide. This review provides insights into these current areas of research, with special emphasis on the interaction of inflammasome components and redox signalling, endoplasmic reticulum stress, and mitochondrial function. We present our findings separately for acute kidney injury and chronic kidney disease. As we strictly divided the results into preclinical and clinical data, this review enables comparison of results from those complementary research specialities. However, it also reveals that knowledge gaps exist, especially in clinical acute kidney injury inflammasome research. Furthermore, patient comorbidities and treatments seem important drivers of inflammasome component alterations in human kidney disease.

Effects of Interleukin-1ß in Glycinergic Transmission at the Central Amygdala.

Interleukin-1ß (IL-1ß) is an important cytokine that modulates peripheral and central pain sensitization at the spinal level. Among its effects, it increases spinal cord excitability by reducing inhibitory Glycinergic and GABAergic neurotransmission. In the brain, IL-1ß is released by glial cells in regions associated with pain processing during neuropathic pain. It also has important roles in neuroinflammation and in regulating NMDA receptor activity required for learning and memory. The modulation of glycine-mediated inhibitory activity via IL-1ß may play a critical role in the perception of different levels of pain. The central nucleus of the amygdala (CeA) participates in receiving and processing pain information. Interestingly, this nucleus is enriched in the regulatory auxiliary glycine receptor (GlyR) ß subunit (ßGlyR); however, no studies have evaluated the effect of IL-1ß on glycinergic neurotransmission in the brain. Hence, we hypothesized that IL-1ß may modulate GlyR-mediated inhibitory activity via interactions with the ßGlyR subunit. Our results show that the application of IL-1ß (10 ng/ml) to CeA brain slices has a biphasic effect; transiently increases and then reduces sIPSC amplitude of CeA glycinergic currents. Additionally, we performed molecular docking, site-directed mutagenesis, and whole-cell voltage-clamp electrophysiological experiments in HEK cells transfected with GlyRs containing different GlyR subunits. These data indicate that IL-1ß modulates GlyR activity by establishing hydrogen bonds with at least one key amino acid residue located in the back of the loop C at the ECD domain of the ßGlyR subunit. The present results suggest that IL-1ß in the CeA controls glycinergic neurotransmission, possibly via interactions with the ßGlyR subunit. This effect could be relevant for understanding how IL-1ß released by glia modulates central processing of pain, learning and memory, and is involved in neuroinflammation.

Is there an Inflammation Role for MYD88 in Rheumatoid Arthritis?

Rheumatoid arthritis (RA) is an autoimmune and inflammatory disease with strong genetic influence, especially upon immune response components. Several cytokines from the toll-like receptors activation pathway display recognized role for RA establishment. However, few studies have verified the role of key mediators such as MYD88 gene and its genetic variants. In the present study, we aim to evaluate the rs6853 functional single-nucleotide variation (SNV) role in RA etiopathogenesis, clinical severity status, and its impact in MYD88 mRNA levels and IL-lß protein levels. For the association study, a total of 423 RA patients and 346 health individuals, enrolled as control, from Northeast and Southeast Brazil were genotyped using specific Taqman probe. For the gene expression assays, we performed a MYD88 rs6853 genotype-guided monocyte cell culture divided into non-stimulated and lypopolysaccharides (LPS)-stimulated cells from healthy individuals. MYD88 gene expression was measured using primer specifics while IL-1ß levels were evaluated by ELISA. We observed that A allele and AA genotype were associated to an increased risk to RA development (OR = 1.60; 95% CI 1.24-2.08; p = 0.0004/OR = 2.83; 95% CI 1.25-6.41; p = 0.0152). The AA genotype exhibited lower MYD88 mRNA levels than GG genotype in non-stimulated monocyte cell culture (FC - 3.83; p = 0.003). Additionally, we verified an increase of IL-1ß levels when AA genotype non-stimulated monocytes were compared to AA genotype LPS-stimulates (p = 0.021). In summary, MYD88 rs6853 polymorphism associated to RA development in our Brazilian cohort and showed influence upon MYD88 mRNA levels' expression and IL-lß production.

Predictive Model of Clinical Attachment Loss and Oral Health-Related Quality of Life through Depressive Symptomatology, Oral Hygiene Habits, and Proinflammatory Biomarkers: A Pilot Study.

Subjective aspects such as oral health-related quality of life (OHRQoL) and depression are important aspects in the periodontal care. The objectives of the study were to test a predictive model of clinical attachment loss and OHRQoL in a pooled sample of dental patients with periodontitis and mental health patients with depressive symptomatology, and test the invariance of the model across both types of patients. Three self-report scales were applied to assess depression, OHRQoL and oral hygiene habits, saliva samples were collected for three proinflammatory biomarkers, and the clinical attachment loss was measured in 35 patients with periodontitis and 26 patients with depressive symptomatology. Data were analyzed through structural equation modeling. The one-group analysis revealed a psychosomatic complaint model of disagreement between the complaint and the clinically observable. In the multi-group analysis, the model was not invariant. It was necessary to introduce a singularity in relation to depressive symptomatology for each population. Thus, a good and equivalent fit was achieved between the six nested models in constraints, as well as equivalent parameters between both types of patients. The study of a dental population in conjunction with a mental health population with a psychosomatic risk factor reveals interesting and unexpected results.

High-Density Lipoproteins Decrease Proinflammatory Activity and Modulate the Innate Immune Response.

Atherosclerosis, a chronic inflammatory disease of the arterial wall, is the leading cause of cardiac disorders and stroke. The onset and progression of these diseases are linked with the inflammatory response, especially NLRP3 inflammasome activation, inducing the production of proinflammatory cytokines, such as interleukin 1ß (IL-1ß). Because high-density lipoproteins (HDLs) have shown significant antiatherogenic and anti-inflammatory properties, we evaluated their immunomodulatory activity in response to cholesterol crystals and other innate immune activators. Human primary monocyte-derived macrophages, THP-1 cells, and murine macrophages were stimulated to activate NLRP3 inflammasome and other pattern recognition receptors, in the presence or absence of HDL. Then, HDL immunomodulatory effects were evaluated through IL-1ß and IL-6 production by enzyme-linked immunosorbent assay. Furthermore, in vivo HDL anti-inflammatory effects were evaluated in a murine model of peritoneal inflammatory infiltration. HDLs have an immunomodulatory effect on different cellular models, including peripheral blood mononuclear cells, THP-1 cells, and murine macrophages, by affecting the activity of innate immunity sensors, such as Toll-like receptors (TLRs), dectin-1, and inflammasomes. HDL reduces the proinflammatory role of cholesterol crystals, nigericin, and other NLRP3 and AIM2 inflammasome agonists, and several TLR agonists, leading to a decreased production of IL-1ß and IL-6. The results suggest that HDLs are highly important in the regulation of the innate immune response and may have a beneficial role in controlling diseases associated with the inflammatory response.

The metabolic and neuroinflammatory changes induced by consuming a cafeteria diet are age-dependent.

OBJECTIVES: To compare the effects of a palatable cafeteria diet on serum parameters and neuroinflammatory markers of young and aged female Wistar rats. METHODS: Three-month-old (young) and 18-month-old (aged) female Wistar rats had access to a cafeteria diet (Caf-Young, Caf-Aged) or a standard chow diet (Std-Young, Std-Aged). RESULTS: The Caf-Young group showed a higher food consumption, weight gain, visceral fat depot, serum insulin and leptin levels, and the insulin resistance index (HOMA-IR) than the Std-Young group. The Caf-Aged group exhibited an increase in interleukin-1 levels in the cerebral cortex and hippocampus. The number of GFAP-positive cells did not differ between the groups, but there was a diet effect in the cerebral cortex and an age effect in the hippocampus. Phospho-tau expression did not differ between the groups. DISCUSSION: The 3- and 18-month-old rats responded differently to a cafeteria diet. Insulin and leptin levels are elevated in young animals fed a cafeteria diet, whereas aged animals are prone to neuroinflammation (indicated by an increase in interleukin-1ß levels). A combination of hypercaloric diet and senescence have detrimental effects on the inflammatory response in the brain, which may predispose to neurological diseases.

CD36 Shunts Eicosanoid Metabolism to Repress CD14 Licensed Interleukin-1ß Release and Inflammation.

Interleukin (IL)-1ß is a potential target for treatment of several inflammatory diseases, including envenomation by the scorpion Tityus serrulatus. In this context, bioactive lipids such as prostaglandin (PG)E2 and leukotriene (LT)B4 modulate the production of IL-1ß by innate immune cells. Pattern recognition receptors (PRRs) that perceive T. serrulatus venom (TsV), and orchestrate LTB4, PGE2, and cyclic adenosine monophosphate (cAMP) production to regulate IL-1ß release are unknown. Furthermore, molecular mechanisms driving human cell responses to TsV remain uncharacterized. Here, we identified that both CD14 and CD36 control the synthesis of bioactive lipids, inflammatory cytokines, and mortality mediated by TsV. CD14 induces PGE2/cAMP/IL-1ß release and inflammation. By contrast, CD36 shunts eicosanoid metabolism toward production of LTB4, which represses the PGE2/cAMP/IL-1ß axis and mortality. Of importance, the molecular mechanisms observed in mice strongly correlate with those of human cell responses to TsV. Overall, this study provides major insights into molecular mechanisms connecting CD14 and CD36 with differential eicosanoid metabolism and inflammation mediated by IL-1ß.

Autophagy Mediates Interleukin-1ß Secretion in Human Neutrophils.

Interleukin-1ß (IL-1ß), a major pro-inflammatory cytokine, is a leaderless cytosolic protein whose secretion does not follow the classical endoplasmic reticulum-to-Golgi pathway, and for which a canonical mechanism of secretion remains to be established. Neutrophils are essential players against bacterial and fungi infections. These cells are rapidly and massively recruited from the circulation into infected tissues and, beyond of displaying an impressive arsenal of toxic weapons effective to kill pathogens, are also an important source of IL-1ß in infectious conditions. Here, we analyzed if an unconventional secretory autophagy mechanism is involved in the exportation of IL-1ß by these cells. Our findings indicated that inhibition of autophagy with 3-methyladenine and Wortmannin markedly reduced IL-1ß secretion induced by LPS + ATP, as did the disruption of the autophagic flux with Bafilomycin A1 and E64d. These compounds did not noticeable affect neutrophil viability ruling out that the effects on IL-1ß secretion were due to cell death. Furthermore, VPS34IN-1, a specific autophagy inhibitor, was still able to reduce IL-1ß secretion when added after it was synthesized. Moreover, siRNA-mediated knockdown of ATG5 markedly reduced IL-1ß secretion in neutrophil-differentiated PLB985 cells. Upon LPS + ATP stimulation, IL-1ß was incorporated to an autophagic compartment, as was revealed by its colocalization with LC3B by confocal microscopy. Overlapping of IL-1ß-LC3B in a vesicular compartment peaked before IL-1ß increased in culture supernatants. On the other hand, stimulation of autophagy by cell starvation augmented the colocalization of IL-1ß and LC3B and then promoted neutrophil IL-1ß secretion. In addition, specific ELISAs indicated that although both IL-1ß and pro-IL-1ß are released to culture supernatants upon neutrophil stimulation, autophagy only promotes IL-1ß secretion. Furthermore, the serine proteases inhibitor AEBSF reduced IL-1ß secretion. Moreover, IL-1ß could be also found colocalizing with elastase, suggesting both some vesicles containing IL-1ß intersect azurophil granules content and that serine proteases also regulate IL-1ß secretion. Altogether, our findings indicate that an unconventional autophagy-mediated secretory pathway mediates IL-1ß secretion in human neutrophils.

Zika Virus Promotes Neuronal Cell Death in a Non-Cell Autonomous Manner by Triggering the Release of Neurotoxic Factors.

Zika virus (ZIKV) has recently caused a worldwide outbreak of infections associated with severe neurological complications, including microcephaly in infants born from infected mothers. ZIKV exhibits high neurotropism and promotes neuroinflammation and neuronal cell death. We have recently demonstrated that N-methyl-d-aspartate receptor (NMDAR) blockade by memantine prevents ZIKV-induced neuronal cell death. Here, we show that ZIKV induces apoptosis in a non-cell autonomous manner, triggering cell death of uninfected neurons by releasing cytotoxic factors. Neuronal cultures infected with ZIKV exhibit increased levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and glutamate. Moreover, infected neurons exhibit increased expression of GluN2B and augmented intracellular Ca2+ concentration. Blockade of GluN2B-containing NMDAR by ifenprodil normalizes Ca2+ levels and rescues neuronal cell death. Notably, TNF-α and IL-1ß blockade decreases ZIKV-induced Ca2+ flux through GluN2B-containing NMDARs and reduces neuronal cell death, indicating that these cytokines might contribute to NMDAR sensitization and neurotoxicity. In addition, ZIKV-infected cultures treated with ifenprodil exhibits increased activation of the neuroprotective pathway including extracellular signal-regulated kinase and cAMP response element-binding protein, which may underlie ifenprodil-mediated neuroprotection. Together, our data shed some light on the neurotoxic mechanisms triggered by ZIKV and begin to elucidate how GluN2B-containing NMDAR blockade can prevent neurotoxicity.

Effects of binge-like ethanol exposure during adolescence on the hyperalgesia observed during sickness syndrome in rats.

Acute and chronic ethanol exposure increases the risk of infection by altering the innate host's defense system. Adolescence is a critical period for brain development. Insults during this period may have long-lasting consequences. The present study investigated the effects of binge-like ethanol exposure in adolescent rats on mechanical hyperalgesia during sickness syndrome that was induced by a systemic injection of lipopolysaccharide (LPS) or an intracerebroventricular (i.c.v.) injection of interleukin-1ß (IL-1ß) after the cessation of ethanol exposure. Male Wistar rats were exposed to ethanol from postnatal day (PND) 25 to PND 38 in a binge-like pattern. Hyperalgesia was assessed on the right hindpaw after an intraperitoneal injection of LPS (5 and 50µg/kg, intraperitoneally) on PND 51 and PND 63 or an i.c.v. or intraplantar (i.pl.) injection of IL-ß (3 and 1ng, respectively) on PND 51. Ethanol exposure during adolescence did not alter mechanical thresholds which increased normally with age. The systemic injection of LPS (0.5-50µg/kg) in adult rats induced dose-related mechanical hyperalgesia. Binge-like ethanol exposure significantly increased mechanical hyperalgesia that was induced by 50µg/kg LPS on PND 51 and 63, which lasted until 24h after the injection. This change was not observed at a lower dose of LPS (5µg/kg). Acute oral treatment with ethanol 24h prior to LPS administration did not alter mechanical hyperalgesia. The i.c.v. injection of IL-1ß (1-10ng) also induced dose-related mechanical hyperalgesia in the right hindpaw in non-exposed animals. In animals that were exposed to binge-like ethanol, the i.c.v. or i.pl. injection of IL-1ß also increased hyperalgesia on PND 51. These results suggest that binge-like ethanol exposure during adolescence causes alterations in the central nervous system that can increase mechanical hyperalgesia that is observed during sickness syndrome, and this effect can be observed until adulthood after the cessation of ethanol exposure.

Sodium thiosulphate attenuates brain inflammation induced by systemic lipopolysaccharide administration in C57BL/6J mice.

It has been demonstrated that peripheral infections accompanied by neuroinflammation may modify brain development or affect normal brain aging and represent major risk factors for the development of neurological disorders. A wide range of synthetic and natural compounds with anti-inflammatory properties have been evaluated in animal models of neuroinflammation and neurodegeneration as an adjuvant therapeutic strategy. In the present study we have demonstrated for the first time that sodium thiosulphate (STS), a known antidote approved for treatment of certain medical conditions, is capable of reducing brain inflammation caused by systemic LPS administration. STS reduced brain levels of pro-inflammatory cytokine interleukin-1ß (IL-1ß), cyclooxygenase-2 (COX-2), ionized calcium binding adaptor molecule 1 (Iba-1) and 18 kDa translocator protein (TSPO) in an animal model of systemic LPS-induced neuroinflammation. In addition, we demonstrated for the first time elevated TSPO expression in retinal ganglion cells layer after peripheral LPS challenge and inhibition of ocular TSPO expression after treatment with STS. We think that STS may be used as an adjuvant anti-inflammatory therapy for many pathological conditions associated with inflammation in the brain.

Effects of Binge-Like Ethanol Exposure During Adolescence on the Febrile Response in Rats.

BACKGROUND: Ethanol (EtOH) exposure during different phases of life may increase the risk of infections and cause alterations in the central nervous system. The present study investigated the effects of binge-like EtOH exposure in adolescent rats on the febrile response that was induced by lipopolysaccharide (LPS) and interleukin-1ß (IL-1ß). METHODS: Male rats were exposed to EtOH from postnatal days 25 to 38 in a binge-like pattern. Fever was induced by LPS (5 and 50 µg/kg, intraperitoneally) and evaluated on postnatal days 51 and 63, or by IL-ß (3 ng) and evaluated on postnatal day 51. Hematological parameters, the status of peritoneal macrophages, and plasma and cerebrospinal IL-1ß levels were also evaluated on postnatal day 51. RESULTS: EtOH exposure during adolescence did not alter normal body temperature. However, a significant reduction in the febrile response that was induced by LPS at both doses was observed on postnatal day 51. However, no changes in the febrile response were observed on postnatal day 63 in EtOH-exposed animals. The febrile response that was induced by intracerebroventricular IL-1ß also significantly decreased in animals that received binge-like EtOH exposure during adolescence. Acute oral treatment with EtOH 24 h prior to LPS administration did not alter the febrile response that was induced by LPS. Binge-like EtOH exposure during adolescence did not alter hematological parameters or the number or viability of peritoneal macrophages. Binge-like EtOH exposure did not alter plasma IL-1ß levels but reduced the cerebrospinal fluid levels of this cytokine. CONCLUSIONS: These results suggest that binge-like EtOH exposure during adolescence causes changes in the central nervous system that can impair the febrile response that can be observed after the cessation of EtOH exposure. These changes were reversible and appeared to involve the LPS/IL-1ß system.

Polymorphism in CRHR1 gene affects the IL-1ß levels in suicidal attempters.

Approximately one million people commit suicide every year, being suicide attempts and ideation even more common. Changes in stress response and activation of the immune system have been associated with suicide risk. Here we investigated the interaction between immune system and HPA axis alterations in the suicide risk, looking for the influence of rs110402 CRHR1 SNP in the IL-1ß levels according to suicide ideation and attempt. This study evaluated 171 subjects of which 15 had suicidal ideation, 20 had suicide attempt and 136 were controls. Genotyping was performed by real-time PCR and IL-1ß levels were measured by ELISA. Our data showed that for each point increase in IL-1ß levels the risk of suicide attempt increased 5% [relative risk = 1.05 (95% CI: 1.0-1.10)]. After sample stratification by rs110402 SNP genotypes, we observed that in subjects carrying the A allele the risk raised to 15% [relative risk = 1.15 (95% CI: 1.03-1.28)], suggesting an apparent effect modification. Thus, this study showed that alterations in CRHR1 gene were associated with higher levels of IL-1ß, and increased risk for suicide, reinforcing the importance of multifactorial interactions of biological markers for psychiatric disorders.

Differential regulation of oxidative stress and cytokine production by endothelin ETA and ETB receptors in superoxide anion-induced inflammation and pain in mice.

The present study investigated whether endothelin-1 acts via ETA or ETB receptors to mediate superoxide anion-induced pain and inflammation. Mice were treated with clazosentan (ETA receptor antagonist) or BQ-788 (ETB receptor antagonist) prior to stimulation with the superoxide anion donor, KO2. Intraplantar treatment with 30 nmol of clazosentan or BQ-788 reduced mechanical hyperalgesia (47% and 42%), thermal hyperalgesia (68% and 76%), oedema (50% and 30%); myeloperoxidase activity (64% and 32%), and overt-pain like behaviours, such as paw flinching (42% and 42%) and paw licking (38% and 62%), respectively. Similarly, intraperitoneal treatment with 30 nmol of clazosentan or BQ-788 reduced leukocyte recruitment to the peritoneal cavity (58% and 32%) and abdominal writhing (81% and 77%), respectively. Additionally, intraplantar treatment with clazosentan or BQ-788 decreased spinal (45% and 41%) and peripheral (47% and 47%) superoxide anion production as well as spinal (47% and 47%) and peripheral (33% and 54%) lipid peroxidation, respectively. Intraplantar treatment with clazosentan, but not BQ-788, reduced spinal (71%) and peripheral (51%) interleukin-1 beta as well as spinal (59%) and peripheral (50%) tumor necrosis factor-alpha production. Therefore, the present study unveils the differential mechanisms by which ET-1, acting on ETA or ETB receptors, regulates superoxide anion-induced inflammation and pain.

Cerebrospinal fluid inflammatory markers in amnestic mild cognitive impairment.

AIMS: Inflammatory processes might play a significant role at the pathophysiology of Alzheimer's disease (AD). Neuroinflammation is characterized by activation of microglia and the release of inflammatory cytokines, such as interleukin (IL)-1ß, IL-6 and tumor necrosis factor-α. Although, it is unknown what the real contribution of these inflammatory markers in the development of AD is. The purpose of the present study was to assess the possible relationship between inflammatory markers in the cerebrospinal fluid (CSF) of amnestic mild cognitive impairment patients (aMCI), aged 60 years or older, and compare with aged healthy controls. METHODS: We examined concentrations of IL-1ß, IL-6 and tumor necrosis factor-α in the CSF of aMCI patients and controls by enzyme immunoassay. aMCI diagnoses were based on anamnesis and Petersen criteria, corroborated by the Clinical Dementia Rating. Cognitive function was assessed by neuropsychological tests. RESULTS: CSF levels of IL-1ß (13.735 vs 22.932 pg/mL; P < 0.001) and tumor necrosis factor-α (1.913 vs 2.627 pg/mL; P = 0.002), but not IL-6 (4.178 vs 5.689 pg/mL; P = 0.106), were significantly reduced in the aMCI samples as compared with controls. Individuals with IL-1ß < 17 pg/mL were at a 7.2 (CI 1.5-36; P: 0.016) increased odds of aMCI. There was a positive correlation between IL-1ß levels and the Consortium to Establish a Registry for Alzheimer's Disease word list score (rs = 0.299; P = 0.046). Linear regression analysis showed that IL-1ß levels might explain 13.7% (ß = 24.545; P = 0.012) of the variance on this Consortium to Establish a Registry for Alzheimer's Disease subscore. CONCLUSION: The present results show a pattern of cytokines expression in the CSF of aMCI patients that might be relevant to the pathogeny of prodromal AD. Geriatr Gerontol Int 2017; 17: 239-245.

Early Life Stress Activates Glial Cells in the Hippocampus but Attenuates Cytokine Secretion in Response to an Immune Challenge in Rat Pups.

OBJECTIVE: Early life stress (ELS) increases the vulnerability to developing psychopathological disorders in adulthood that are accompanied by brain inflammatory processes. However, it is not known how a combined double hit (stress and immune) at an early age affects the response of the neuroimmune system. Here we investigated the effect of periodic maternal separation (MS) followed by administration of lipopolysaccharide (LPS) on glial cells in the CA3 region and hilus of the hippocampus and on cytokine release on postnatal day (PN) 15. METHODS: Male rat pups were subjected to MS (3 h/day, PN1-14). MS and control pups received a single LPS injection (1 mg/kg of body weight) on PN14. They were subjected to an open field test 1 h later. The pups were sacrificed 90 min after LPS injection (PN14) or on PN15 for cytokine or immunohistological analyses, respectively. RESULTS: LPS reduced the locomotion and induced high corticosterone levels in treated pups. MS or LPS reduced microglial density and activated microglial cells in the hippocampal CA3 and hilus regions. Microglial activation was highest in MS-LPS pups. The astrocyte density was mildly reduced by MS or LPS in the CA3 region and hilus, but the reduction was maximal in MS-LPS pups. LPS increased the secretion of plasmatic interleukin (IL)-1ß, tumor necrosis factor-α, and IL-6, and of hippocampal IL-1ß protein, but these were attenuated in MS-LPS pups. CONCLUSION: Although MS and LPS activate neuroimmune cells, stress attenuates the hippocampal and peripheral cytokine response to LPS through an as-yet unidentified adaptive mechanism. These results provide information regarding the neurobiology of stress and inflammation.