IL-6 and TNF-α serum levels are associated with early death in community-acquired pneumonia patients

Community-acquired pneumonia (CAP) is amongst the leading causes of death worldwide. As inflammatory markers, cytokines can predict outcomes, if interpreted together with clinical data and scoring systems such as CURB-65, CRB, and Acute Physiology and Chronic Health Evaluation II (APACHE II). The aim of this study was to determine the impact of inflammatory biomarkers on the early mortality of hospitalized CAP patients. Twenty-seven CAP patients needing hospitalization were enrolled for the study and samples of interleukin-1 (IL-1) and interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), C-reactive protein (CRP), and homocystein were collected at the time of admission (day 1) as well as on the seventh day of the treatment. There was a significant reduction in the levels of IL-6 between the first and the second collections. Median IL-6 values decreased from 24 pg/mL (day 1) to 8 pg/mL (day 7) (P=0.016). The median levels of TNF-α were higher in patients: i) with acute kidney injury (AKI) (P=0.045), ii) requiring mechanical ventilation (P=0.040), iii) with short hospital stays (P=0.009), iv) admitted to the intensive care unit (ICU) (P=0.040), v) who died early (P=0.003), and vi) with worse CRB scores (P=0.013). In summary, IL-6 and TNF-α levels were associated with early mortality of CAP patients. Longer admission levels demonstrated greater likelihood of early death and overall mortality, necessity of mechanical ventilation, and AKI.

The effects of 6-gingerol on proliferation, differentiation, and maturation of osteoblast-like MG-63 cells

We investigated whether 6-gingerol affects the maturation and proliferation of osteoblast-like MG63 cells in vitro. Osteoblast-like MG63 cells were treated with 6-gingerol under control conditions, and experimental inflammation was induced by tumor necrosis factor-α (TNF-α). Expression of different osteogenic markers and cytokines was analyzed by real-time PCR, Western blotting, and enzyme-linked immunosorbent assay. In addition, alkaline phosphatase (ALP) enzyme activity and biomineralization as markers for differentiation were measured. Treatment with 6-gingerol resulted in insignificant effects on the proliferation rate. 6-Gingerol induced the differentiation of osteoblast-like cells with increased transcription levels of osteogenic markers, upregulated ALP enzyme activity, and enhanced mineralized nodule formation. Stimulation with TNF-α led to enhanced interleukin-6 and nuclear factor-κB expression and downregulated markers of osteoblastic differentiation. 6-Gingerol reduced the degree of inflammation in TNF-α-treated MG-63 cells. In conclusion, 6-gingerol stimulated osteoblast differentiation in normal physiological and inflammatory settings, and therefore, 6-gingerol represents a promising agent for treating osteoporosis or bone inflammation.

Caractérisation du motif acidique de la sous-unité p28 de l’IL-27 et étude des propriétés partagées entre cette protéine, le CNTF, CLC/CLF et l’interleukine-6

L’interleukine 6 (IL-6) est une cytokine qui joue un rôle essentiel dans l’inflammation. Son récepteur (IL-6R) est composé de la chaîne non signalétique IL-6Rα et de la chaîne transductrice du signal gp130, commune aux cytokines de la famille IL-6. La liaison de l’IL-6 à son récepteur permet l’activation de plusieurs voies de signalisation, notamment des voies Jak/STAT1 et préférentiellement Jak/STAT3. De façon complémentaire, nous avons démontré que l’IL-6 est capable d’activer la voie Jak/STAT5 dans les lymphocytes T CD4. L’activation de cette voie de signalisation pourrait être impliquée dans le rétrocontrôle des effets pro-inflammatoires de l’IL-6 sur les cellules T CD4. Le facteur neurotrophique ciliaire (CNTF) et la « cardiotrophin-like cytokine/cytokine-like factor 1 » (CLC/CLF) sont deux cytokines de la famille de l’IL-6 qui signalent à travers un récepteur commun, le récepteur au CNTF (CNTFR), composé du CNTFRα, « leukaemia inhibitory factor receptor β » (LIFRβ) et gp130. Toutes deux exercent des actions au niveau du système immunitaire, or la chaîne CNTFRα de leur récepteur n’y est pas exprimée. Il a été montré que le CNTFR humain peut également activer un récepteur formé des sous-unités IL-6Rα, LIFRβ et gp130. Nous avons comparé les effets du CNTF et du CLC/CLF de souris sur des transfectants exprimant LIFRβ et gp130 et les chaines α connues de la famille IL-6 (IL-6Rα, IL-11Rβ et CNTFRα). Nos résultats indiquent que le CNTF de souris, comme le CNTF humain est capable d’activer un récepteur formé de l’IL-6Rα, LIFRβ et gp130. Toutefois cette propriété n’est pas partagée par CLC/CLF et le récepteur impliqué dans les effets de cette cytokine sur le système immunitaire reste donc à identifier. L’IL-27 appartient à la famille de l’IL-6 composée d’une sous-unité cytokinique, p28, associée à un récepteur soluble « l’Epstein-Barr virus-induced gene 3» (EBI3). La sous-unité p28 peut s’associer avec le récepteur soluble CLF pour former une cytokine capable d’activer les lymphocytes T. Dans le but de caractériser cette cytokine, nous avons montré que p28/CLF agit aussi sur les lymphocytes B et permet leur différenciation en plasmocytes. Le partage de l’IL-6R par l’IL-6 et p28/CLF semble être à l’origine de la similarité des effets de ces deux cytokines. De plus, nous avons observé des effets semblables à ceux de l’IL-6 suite à l’association de la sous-unité p28 seule avec la chaîne IL-6Rα. En effet, afin de mieux caractériser la cytokine p28/CLF, nous avons étudié les effets dus au recrutement de la chaîne IL-6Rα par la sous-unité p28. Les cytokines de la famille de l’IL-6 sont composées de quatre hélices α disposées de façon anti-parallèle deux à deux. La sous-unité p28 possède, au niveau d’une boucle reliant deux hélices α, un motif de plusieurs acides glutamiques consécutifs (motif polyE) qui n’est retrouvé dans aucune autre cytokine de cette famille. Nous avons démontré que ce motif est impliqué dans la liaison de cette sous-unité avec l’hydroxyapatite et l’os. Cette caractéristique de p28 pourrait permettre un ciblage de l’IL-27 (p28/EBI3) et de p28/CLF préférentiellement vers la niche endostéale des cellules souches et des cellules immunitaires.

IL-6 and TNF-alpha production during active canine visceral leishmaniasis

We investigated the production of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) during canine visceral leishmaniasis (VL) to gain a better understanding of the role of such multi-functional cytokines in parasite resistance. IL-6 and TNF-alpha levels were measured by capture ELISA in sera from 8 healthy dogs from a non-endemic area (control group) and in sera from 16 dogs from Aracatuba, SP, Brazil, an area endemic for leishmaniosis. The dogs from the endemic area were selected by positive ELISA serology against total Leishmania chagasi antigen, positive spleen imprints for Leishmania, and the presence of at least three clinical signs associated with active visceral leishmaniasis (fever, dermatitis, lymphoadenopathy, onychogryphosis, weight loss, cachexia, locomotory difficulty, conjunctivitis, epistaxis, hepatosplenomegaly, edema, and apathy).Enhanced systemic IL-6 production was found in sera from dogs with the active disease compared to healthy dogs (t-test, P < 0.05). In contrast, TNF-alpha did not differ between the two groups studied. There was no correlation between IL-6 production and anti-leishmanial antibody titers in the sera. Our findings suggest that IL-6 is a good marker of active disease during leishmaniasis, and that other cytokines may be involved in the hypergammaglobulinemia characteristic of canine visceral leishmaniasis. (c) 2006 Published by Elsevier B.V.

Interleukin-4 and interleukin-13 inhibit the expression of leukemia inhibitory factor and interleukin-11 in fibroblasts

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Stimulation of IL-6 Cytokines in Fibroblasts by Toll-like Receptors 2

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

p38 MAPK regulates IL-1β induced IL-6 expression through mRNA stability in osteoblasts

Osteoblast-derived IL-6 functions in coupled bone turnover by supporting osteoclastogenesis favoring bone resorption instead of bone deposition. Gene regulation of IL-6 is complex occurring both at transcription and post-transcription levels. The focus of this paper is at the level of mRNA stability, which is important in IL-6 gene regulation. Using the MC3T3-E1 as an osteoblastic model, IL-6 secretion was dose dependently decreased by SB203580, a p38 MAPK inhibitor. Steady state IL-6 mRNA was decreased with SB203580 (2 μM) ca. 85% when stimulated by IL-1β (1-5 ng/ ml). These effects require de novo protein synthesis as they were inhibited by cycloheximide. p38 MAPK had minor effects on proximal IL-6 promoter activity in reporter gene assays. A more significant effect on IL-6 mRNA stability was observed in the presence of SB203580. Western blot analysis confirmed that SB203580 inhibited p38 MAP kinase, in response to IL-1β in a dose dependent manner in MC3T3-E1 cells. Stably transfected MC3T3-E1 reporter cell lines (MC6) containing green fluorescent protein (GFP) with the 3′untranslated region of IL-6 were constructed. Results indicated that IL-1β, TNFα, LPS but not parathyroid hormone (PTH) could increase GFP expression of these reporter cell lines. Endogenous IL-6 and reporter gene eGFP-IL-6 3′UTR mRNA was regulated by p38 in MC6 cells. In addition, transient transfection of IL-6 3′UTR reporter cells with immediate upstream MAP kinase kinase-3 and -6 increased GFP expression compared to mock transfected controls. These results indicate that p38 MAPK regulates IL-1β-stimulated IL-6 at a post transcriptional mechanism and one of the primary targets of IL-6 gene regulation is the 3′UTR of IL-6.

Infantile epileptic encephalopathy with hypsarrhythmia (infantile spasms/west syndrome) and immunity

West syndrome is a severe epilepsy, occurring in infancy, that comprises epileptic seizures known as spasms, in clusters, and a unique EEG pattern, hypsarrhythmia, with psychomotor regression. Maturation of the brain is a crucial component. The onset is within the first year of life, before 12 months of age. Patients are classified as cryptogenic (10 to 20%), when there are no known or diagnosed previous cerebral insults, and symptomatic (80 to 90%), when associated with pre-existing cerebral damages. The time interval from a brain insult to infantile spasms onset ranged from 6 weeks to 11 months. West syndrome has a time-limited natural evolutive course, usually disappearing by 3 or 4 years of age. In 62% of patients, there are transitions to another age-related epileptic encephalopathies, the Lennox-Gastaut Syndrome and severe epilepsy with multiple independent foci. Spontaneous remission and remission after viral infections may occur. Therapy with ACTH and corticosteroids are the most effective. Reports about intravenous immunoglobulins action deserve attention. There is also immune dysfunction, characterized mainly by anergy, impaired cell-mediated immunity, presence of immature thymocytes in peripheral blood, functional impairment of T lymphocytes induced by plasma inhibitory factors, and altered levels of immunoglobulins. Changes in B lymphocytes frequencies and increased levels of activated B cells have been reported. Sensitized lymphocytes to brain extract were also described. Infectious diseases are frequent and may, sometimes, cause fatal outcomes. Increase of pro-inflamatory cytokines in serum and cerebrospinal fluid of epileptic patients were reported. Association with specific HLA antigens was described by several authors (HLA-DR7, HLA-A7, HLA-DRw52, and HLA-DR5). Auto-antibodies to brain antigens, of several natures (N-methyl-d-aspartate glutamate receptor, gangliosides, brain tissue extract, synaptic membrane, and others), were described in epileptic patients and in epileptic syndromes. Experimental epilepsy studies with anti-brain antibodies demonstrated that epileptiform discharges can be obtained, producing hyperexcitability leading to epilepsy. We speculate that in genetically prone individuals, previous cerebral lesions may sensitize immune system and trigger an autoimmune disease. Antibody to brain antigens may be responsible for impairment of T cell function, due to plasma inhibitory effect and also cause epilepsy in immature brains. © 2008 Bentham Science Publishers Ltd.

Effects of active smoking on airway and systemic inflammation profiles in patients with chronic obstructive pulmonary disease

Background: The markers that characterize local and systemic inflammation in chronic obstructive pulmonary disease (COPD) remain unclear, as do their correlations with smoking status and presence of disease. The aim of this study was to assess markers of inflammation in the peripheral blood and airways of current smokers without COPD, of current smokers with COPD and of ex-smokers with COPD. METHODS: In this study, 17 current smokers with COPD (mean age: 58.2 ± 9.6 years; mean forced expiratory volume in 1 second [FEV1]: 56.1 ± 15.9%), 35 ex-smokers with COPD (mean age: 66.3 ± 7.3 years; mean FEV1: 47.9 ± 17.2%) and 20 current smokers without COPD (mean age: 49.1 ± 6.2 years; mean FEV1: 106.5 ± 15.8%) were evaluated. Spirometry findings, body composition and serum/induced sputum concentrations of tumor necrosis factor α (TNF-α), interleukin (IL)-6, IL-8 and IL-10, together with serum C-reactive protein (CRP) levels, were assessed. RESULTS: Serum TNF-α concentration was higher in all current smokers than in ex-smokers with COPD. In current smokers without COPD, serum CRP level was lower than in ex-smokers with COPD and significantly lower than in current smokers with COPD. Sputum TNF-α concentration was higher in current and ex-smokers with COPD than in current smokers without COPD. Multiple regression analyses showed that serum TNF-α was associated with active smoking, and serum CRP and sputum TNF-α were associated with COPD diagnosis. CONCLUSIONS: Smoking is associated with higher systemic inflammation in patients with COPD. Current findings also support the hypothesis that smoking and COPD have different effects on the regulation of airway and systemic inflammatory processes. © 2013 Lippincott Williams and Wilkins.

Interleucina 6 e proteinograma sérico de ovinos submetidos à endotoxemia experimental

Pós-graduação em Ciência Animal - FMVA

Efeito de Interleucina-6 sobre a atividade fungicida e produção de citocinas por monócitos humanos, infectados in vitro com cepa virulenta de paracoccidioides brasiliensis

Pós-graduação em Patologia - FMB

Evolução da interleucina 6 e da proteína C-Reativa em pacientes com DPOC no período de três anos

Pós-graduação em Fisiopatologia em Clínica Médica - FMB

The role of IL-6 on apical periodontitis: a systematic review

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Procalcitonina e interleicina-6 em crianças com diagnóstico de sepse e choque séptico

Sepse é causa comum de mortalidade e morbidade em unidades de tratamento intensivo, sendo atualmente entendida como a resposta sistêmica à infecção, resposta esta caracterizada por duas ou mais das seguintes manifestações: temperatura corporal > 38°C ou < 36°C; taquicardia; taquipnéia; e alteração da contagem de células brancas (leucocitose ou leucopenia) ou mais de 10% de formas imaturas. Entretanto, tem sido descrito que os elementos que caracterizam a resposta sistêmica são muito sensíveis, insuficientemente específicos e não levam em consideração o avanço do entendimento da fisiopatologia da doença. Além disso, a sepse tem fisiopatologia complexa, o que dificulta ainda mais o diagnóstico, principalmente em crianças. O diagnóstico rápido e a instituição de tratamento o mais cedo possível são imperativos nos pacientes sépticos. Consequentemente, vários marcadores laboratoriais têm sido estudados, sendo que dos vários mediadores envolvidos na sepse, procalcitonina (PCT) e interleucina-6 (IL-6) têm despertado interesse pela possibilidade de auxiliar no diagnóstico e no estabelecimento da gravidade de pacientes adultos com sepse ou choque séptico, sendo que a PCT já foi incluída entre os critérios diagnósticos de sepse nestes indivíduos. Em pediatria... (Resumo completo, clicar acesso eletrônico abaixo)

In vivo evaluation of the inflammatory response and IL-6 immunoexpression promoted by Biodentine and MTA Angelus

Aim To evaluate the inflammatory process induced by Biodentine and mineral trioxide aggregate (MTA) in rat subcutaneous tissues. Methodology A polyethylene tube filled with Biodentine (n = 20) or MTA (n = 20) was placed into the dorsal subcutaneous of forty male rats; in the control group (CG; n = 20), empty tubes were implanted. After 7, 15, 30 and 60 days, the polyethylene tubes surrounded by connective tissue were fixed and embedded in paraffin. The number of inflammatory cells was estimated in HE-stained sections; numerical density of interleukin-6 (IL-6)-immunolabelled cells was also performed. The differences amongst the groups were analysed statistically by Tukey's test (P ≤ 0.05). Results A high number of inflammatory cells and IL-6-positive cells were observed at 7 days, in all groups; however, in the Biodentine group, the number of inflammatory cells and IL-6-immunolabelled cells was significantly higher (P ≤ 0.05) in comparison with the other groups at 7 and 15 days. In the capsules of animals from all groups, a gradual and significant reduction (P ≤ 0.05) of these parameters was seen over time. At 60 days, the capsules exhibited numerous fibroblasts and bundles of collagen fibres; in addition, the number of IL-6-positive cells was not significantly different amongst Biodentine, MTA and control groups. Conclusions There was a significant regression in the inflammatory reaction in the capsules indicating, therefore, that Biodentine is a biocompatible material.