[Inflammation mediators and control of food intake].
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Anorexia↗
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Results for “Inflammation Mediators”
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Gamma interferon-mediated inflammation is associated with lack of protection from intravaginal simian immunodeficiency virus SIVmac239 challenge in simian-human immunodeficiency virus 89.6-immunized rhesus macaques.
Although gamma interferon (IFN-gamma) is a key mediator of antiviral defenses, it is also a mediator of inflammation. As inflammation can drive lentiviral replication, we sought to determine the relationship between IFN-gamma-related host immune responses and challenge virus replication in lymphoid tissues of simian-human immunodeficiency virus 89.6 (SHIV89.6)-vaccinated and unvaccinated rhesus macaques 6 months after challenge with simian immunodeficiency virus SIVmac239. Vaccinated-protected monkeys had low tissue viral RNA (vRNA) levels, vaccinated-unprotected animals had moderate tissue vRNA levels, and unvaccinated animals had high tissue vRNA levels. The long-term challenge outcome in vaccinated monkeys was correlated with the relative balance between SIV-specific IFN-gamma T-cell responses and nonspecific IFN-gamma-driven inflammation. Vaccinated-protected monkeys had slightly increased tissue IFN-gamma mRNA levels and a high frequency of IFN-gamma-secreting T cells responding to in vitro SIVgag peptide stimulation; thus, it is likely that they could develop effective anti-SIV cytotoxic T lymphocytes in vivo. In contrast, both high tissue IFN-gamma mRNA levels and strong in vitro SIV-specific IFN-gamma T-cell responses were detected in lymphoid tissues of vaccinated-unprotected monkeys. Unvaccinated monkeys had increased tissue IFN-gamma mRNA levels but weak in vitro anti-SIV IFN-gamma T-cell responses. In addition, in lymphoid tissues of vaccinated-unprotected and unvaccinated monkeys, the increased IFN-gamma mRNA levels were associated with increased Mig/CXCL9, IP-10/CXCL10, and CXCR3 mRNA levels, suggesting that increased Mig/CXCL9 and IP-10/CXCL10 expression resulted in recruitment of CXCR3(+) activated T cells. Thus, IFN-gamma-driven inflammation promotes SIV replication in vaccinated-unprotected and unvaccinated monkeys. Unlike all unvaccinated monkeys, most monkeys vaccinated with SHIV89.6 did not develop IFN-gamma-driven inflammation, but they did develop effective antiviral CD8(+)-T-cell responses.
AIDS Vaccines↗
Jak/STAT/SOCS signaling circuits and associated cytokine-mediated inflammation and hypertrophy in the heart.
Cytokines are important mediators of cardiac disease. Accumulating evidence indicates that members of the interleukin-6 family of cytokines promote cardiac hypertrophy through the activation of the Janus kinase-signal transducer and activator of transcription (Jak/STAT) pathway. Aberrant Jak/STAT signaling may promote progression from hypertrophy to heart failure. Suppressor of cytokine signaling (SOCS) proteins are underexplored, negative regulators of Jak/STAT signaling. SOCS proteins may also interact with other inflammatory pathways known to affect cardiac function. A better understanding of the therapeutic potential of these proteins may lead to the controlled progression of heart failure and the limitation of myocardial depression. This review summarizes the cardiophysiological effect of the IL-6 cytokine family, outlines the mechanistic pathway of Jak/STAT signaling, explores the regulatory role of SOCS proteins in the heart, and discusses the potential of using SOCS proteins clinically.
Animals↗
INFLAMMATION MEDIATORS AND THE INFLAMMATORY REACTION.
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Anti-Allergic Agents↗
[The role of inflammation mediators in bronchial asthma and chronic obstructive pulmonary disease].
Bronchial asthma and chronic obstructive pulmonary disease (COPD) are chronic inflammatory diseases of the bronchial tree. Some products of eosinophils, neutrophils and other cells have been implicated in causing bronchial mucosal damage and may play important role in monitoring degree of airway inflammation and differentiation between bronchial asthma and COPD. The author described some of them.
Asthma↗
Pathogenesis of bronchopulmonary dysplasia: the role of interleukin 1beta in the regulation of inflammation-mediated pulmonary retinoic acid pathways in transgenic mice.
BACKGROUND: Pulmonary inflammation, increased production of the inflammatory cytokine interleukin-1beta (IL-1beta), and vitamin A deficiency are risk factors for the development of bronchopulmonary dysplasia (BPD) in premature infants. To determine the mechanisms by which IL-1beta influences lung development, we have generated transgenic mice in which human IL-1beta is expressed in the lung epithelium with a doxycycline-inducible system controlled by the Clara cell secretory protein promoter. Perinatal IL-1beta production in these mice causes a phenotype that is strikingly similar to BPD. Pulmonary pathology in the mice shows inflammation, lack of alveolar septation, and impaired vascular development of the lung, similar to the histological characteristics of BPD. Retinoic acid (RA), one of the most biologically active derivatives of vitamin A, increases septation. Proteins involved in mediating the cellular responses to RA include the cellular retinoic acid binding proteins CRABP-I and CRABP-II and the nuclear retinoic acid receptors RAR-alpha, RAR-beta, and RAR-gamma. OBJECTIVE: To test the hypothesis that IL-1beta inhibits the expression of proteins involved in mediating the cellular response to RA. METHODS: The mRNA expression of CRABP-I, CRABP-II, RAR-alpha1, RAR-beta2, RAR-beta4, and RAR-gamma2 was studied with real-time RT-PCR on gestational day 18, and postnatal days 0, 1, 5, and 7 in IL-1beta-expressing mice and their control littermates. In addition, immunohistochemistry for CRABP-I was performed. RESULTS: IL-1beta decreased the mRNA expression and protein production of CRABP-I as well as the mRNA expression of RAR-gamma2. In contrast, no differences between IL-1beta-expressing and control mice were detected in the expression of CRABP-II, RAR-alpha1, RAR-beta2, or RAR-beta4. CONCLUSION: The present study demonstrates for the first time a link between inflammation and the retinoic acid pathway. Inhibition of CRABP-I and RAR-gamma2 expression may be one mechanism by which inflammation prevents alveolar septation. The therapeutic potential of RA in promoting septation in the setting of perinatal lung inflammation deserves further investigation.
Animals↗
Homeostatic role of interferons conferred by inhibition of IL-1-mediated inflammation and tissue destruction.
In addition to their well known immune and proinflammatory activities, IFNs possess homeostatic functions that limit inflammation and tissue destruction in a variety of conditions such as arthritis, osteolysis, and multiple sclerosis. The mechanisms underlying the homeostatic actions of IFNs are not well understood. We report here that both type I and type II IFNs (IFN-alpha, IFN-beta, and IFN-gamma, respectively) suppressed a broad range of proinflammatory and tissue-destructive activities of IL-1, including induction of inflammatory mediators, production of matrix metalloproteinases, macrophage tissue invasion, and cartilage degradation. IFN-alpha attenuated IL-1-mediated cell recruitment in vivo. IFNs completely suppressed the activation of IL-1 signal transduction pathways in macrophages. The mechanism of IFN-mediated inhibition of IL-1 action and signaling was modulation of IL-1R expression, which was also observed in vivo. IFN-gamma-mediated down-regulation of IL-1R type I expression was dependent on Stat1, a transcription factor typically considered to be a key mediator of macrophage activation by IFNs. These results identify cellular and molecular mechanisms that contribute to the homeostatic role of IFNs in limiting inflammation and associated tissue destruction.
Animals↗
The role of very late antigen-1 in immune-mediated inflammation.
The alpha1beta1 integrin, also known as "very late antigen" (VLA)-1, is normally expressed on mesenchymal cells, some epithelial cells, activated T cells, and macrophages, and interacts, via the I-domain of the extracellular domain of the alpha1 subunit, with collagen molecules in the extracellular matrix (ECM). By "outside-in" transmembranal signaling to the interior of the cell, it mediates adhesion, migration, proliferation, remodeling of the ECM, and cytokine secretion by endothelial cells, mesangial cells, fibroblasts, and immunocytes. Importantly, its expressions and functions are enhanced by inflammatory cytokines including interferon (IFN)gamma and tumor necrosis factor (TNF)alpha, thus augmenting angiogenesis and fibrosis linked, in particular, to inflammation. Moreover, within the immune system, VLA-1 marks effector memory CD4+ and CD8+ T cells that are retained in extralymphatic tissues by interactions of the integrin with collagen and produce high levels of IFNgamma. Thus, immune-mediated inflammation in vivo is inhibited by blockade of the VLA-1-collagen interaction in experimental animal models of arthritis, colitis, nephritis, and graft versus host disease (GVHD), suggesting that inhibiting the interaction of the alpha1 I-domain with its ligands or modulating "outside-in" signaling by VLA-1 would be a useful approach in the human diseases simulated by these experimental models.
Animals↗
Activation of HLA-DR and interleukin-6 gene transcription in resting T cells via the CD2 molecule: relevance to chronic immune-mediated inflammation.
Only a minority of T cells at cell-mediated immune lesions are antigen specific. In the lesions of human autoimmune disease, such as the synovial membrane in rheumatoid arthritis, the T cells are activated as shown by a variety of phenotypic and functional changes including the expression of HLA-DR and the production of interleukin-6 (IL-6). The stimulatory pathway involved is unknown but does not seem to involve the T-cell receptor. Alternative pathways of activation which may be involved include the CD2 molecule. It is shown that the formation of sheep red blood cell (SRBC) rosettes with resting T cells from human peripheral blood, which is equivalent to CD2/LFA-3 binding, leads to the de novo transcription of the HLA-DR and IL-6 genes and the expression of HLA-DR on the surface of the T cells. There was no transcription of the interleukin-2 (IL-2) or the interleukin-2 receptor (IL-2R) genes and Tac expression was not seen. The rosetted T cells did not proliferate. These are all characteristics of T cells at chronic inflammatory sites. It is concluded that receptor-ligand interactions between CD2/LFA-3, which are expressed in increased amounts in the rheumatoid joint, may be one pathway by which antigen non-specific T cells are recruited as effector cells in lesions of human autoimmune disease.
Antigens, Differentiation, T-Lymphocyte↗
Inhibition of microglial activation by the herbal flavonoid baicalein attenuates inflammation-mediated degeneration of dopaminergic neurons.
Accumulating evidence has suggested that inflammation in the brain participates in the pathogenesis of Parkinson's disease (PD). Therefore, anti-inflammatory therapy has attracted much attention as novel interference to neurodegenerative diseases. Baicalein, a major flavonoid extracted from a traditional Chinese herb Scutellaria baicalensis Georgi (Huangqin), possesses potent anti-inflammatory and antioxidant properties. To test the potential neuroprotective effect of baicalein on dopaminergic neurons, primary midbrain neuron-glia cultures from E-14 rat embryos were used. Cultures were pretreated with baicalein for 30 min prior to stimulation with lipopolysaccharide (LPS, 10 ng/ml). LPS leads to massive activation of microglial cells revealed by OX-42 immunostaining, and produced excessive quantities of NO. Excessive elevation of superoxide level was also observed in enriched-microglia after stimulating with LPS. LPS-induced damage to dopaminergic neurons was evaluated by uptake capacity for [3H]dopamine and tyrosine hydroxylase (TH)-immunocytochemistry. Pretreatment with baicalein concentration-dependently attenuated LPS-induced decrease in [3H]dopamine uptake and loss of TH-immunoreactive (TH-ir) neurons, which the maximum protective effect was observed at the concentration of 5 microM. Post-treatment with baicalein (5 microM) was also shown to be effective even if baicalein administered up to 2 h later than LPS application. Morphological study shows that baicalein (5 microM) almost completely blocked LPS-induced activation of microglia. Excessive production of TNF(alpha) and free radicals such as NO and superoxide by LPS stimulation were also attenuated by baicalein at a concentration-dependent pattern. The present study indicates that baicalein exerts potent neuroprotective effect on LPS-induced injury of dopaminergic neurons. We hypothesize that the inhibition of LPS-induced production of NO and free radicals from microglia may underlie the mechanism of baicalein's neuroprotection.
Animals↗
[Inflammation mediators in pathogenesis of infection-toxic shock of meningococcal etiology].
Up-to-date advances made in understanding of the events underlying meningococcal infection-toxic shock (ITS) are reviewed. Endotoxin properties, its interaction with transport protein and specific membrane receptors entailing activation of macrophages and secretion of cytokines TNF and IL-1 are described. Both of them are considered as major mediators of ITS. Recent information about activation of complement and coagulation cascades, changes of kinetic and functional properties of polymorphonuclear leukocytes are summarized. As to secondary mediators, the emphasis is placed on bioregulatory system L-arginine-NO. A scheme of pathogenesis of meningococcal ITS is provided. The latter is corresponding both clinically and morphologically to other endotoxin shocks and its peculiarities in excessive activation of coagulation system.
Humans↗
[Leukotrienes as inflammation mediators].
Leukotrienes are biologically active metabolites derived from arachidonic acid playing an important role in inflammatory responses. There are two main groups of leukotrienes: dihydroxyleukotrienes (LTB4) and cysteinyl-leukotrienes (LTC4, LTD4, LTE4). By activating specific G-protein coupled receptors, leukotrienes take part in immune responses, like activation and chemotaxis of leukocytes. Several studies have shown that leukotrienes may play a significant role in pathomechanisms of inflammatory diseases of human airways, skin, digestive tract and heart.
Chemotaxis↗
Kinetics of the development and recovery of the lung from IgE-mediated inflammation: dissociation of pulmonary eosinophilia, lung injury, and eosinophil-active cytokines.
Events occurring up to 16 d after antigen challenge were characterized using a novel protocol employing four bronchoscopies, two segmental antigen challenge (SAC) procedures (on Days 1 and 2), and six bronchoalveolar lavages (BALs) (on Days 1, 2, 9, and 16) in three groups: ragweed allergic asthmatics with dual phase airway reactions (AA-D), allergic asthmatics with a single early airway reaction (AA-S), and nonallergic nonasthmatic control subjects. In AA-D subjects, SAC produced a marked eosinophilic inflammatory response at 24 h associated with eosinophil degranulation (eosinophil cationic protein [ECP] in BAL fluid) and lung injury, which largely resolved by Day 16. When the second antigen-challenged segment (SAC performed on Day 2) was lavaged 7 d after challenge (Day 9), a persistent pulmonary eosinophilia was noted accompanied by minimal elevations in ECP and albumin. Eosinophil-active cytokines showed unique patterns: interleukin-5 (IL-5) increased in the antigen segment on Day 2 then returned to baseline after 7 d; granulocyte-macrophage colony-stimulating factor (GM-CSF) peaked at Day 2 but was persistently elevated throughout Day 16 in antigen segments, and increased in control segments at late time points; IL-3 levels were constant and similar in antigen and control segments. Changes were specific to AA-D subjects in comparison with control subjects. Elements of the IgE-mediated pulmonary inflammatory response differ markedly in their development and resolution.
Adult↗
[The production of inflammation mediators by mouse peritoneal cells under conditions of combined exposure to staphylococcal enterotoxin and lipopolysaccharide].
The influence of staphylococcal enterotoxin of type A (SEA) and enterobacterial lipopolysaccharide (LPS) on the production of tumor necrosis factor alpha (TNF alpha), gamma-interferon and active forms of oxygen by mouse peritoneal cells was studied. Both SEA and LPS, when injected to animals, produced stimulating influence on the oxygen metabolism of phagocytizing cells. The highest toxic doses of LPS induced the maximal generation of oxygen radicals. Under the conditions of the development of lethal toxic shock, i.e. after the combined injection of SEA and LPS, the synergic activation of oxygen metabolism was observed, which was also manifested by the pronounced production of TNF alpha and the increased synthesis of gamma-interferon.
Animals↗
Stat4 is expressed in activated peripheral blood monocytes, dendritic cells, and macrophages at sites of Th1-mediated inflammation.
Stat4 is a key transcription factor involved in promoting cell-mediated immunity, whose expression in mature cells has been reported to be restricted to T and NK cells. We demonstrate here, however, that Stat4 expression is not restricted to lymphoid cells. In their basal state, monocytes do not express Stat4. Upon activation, however, IFN-gamma- and LPS-treated monocytes and dendritic cells express high levels of Stat4. Monocyte-expressed Stat4 in humans is phosphorylated in response to IFN-alpha, but not IL-12. In contrast, the Th2 cytokines, IL-4 and IL-10, specifically down-regulate Stat4 expression in activated monocytes, while having little effect on Stat6 expression. Moreover, macrophages in synovial tissue obtained from patients with rheumatoid arthritis express Stat4 in vivo, suggesting a potential role in a prototypical Th1-mediated human disease. IFN-alpha-induced Stat4 activation in human monocytes represents a previously unrecognized signaling pathway at sites of Th1 inflammation.
Arthritis, Rheumatoid↗
Down-regulation of the aberrant expression of the inflammation mediator high mobility group box chromosomal protein 1 in muscle tissue of patients with polymyositis and dermatomyositis treated with corticosteroids.
OBJECTIVE: High mobility group box chromosomal protein 1 (HMGB-1) is an endogenous nuclear protein that can be translocated to the cytoplasm and then released extracellularly. It can induce tumor necrosis factor and interleukin-1 production in myeloid cells. Increased expression of these 2 cytokines has been observed in muscle tissue of patients with polymyositis (PM) and dermatomyositis (DM). The present study was therefore undertaken to investigate how HMGB-1 is expressed in muscle tissue of patients with myositis and, if so, whether such expression is modulated by prednisolone therapy. METHODS: Muscle biopsy specimens from 5 patients with PM and 4 patients with DM, obtained before and 3-6 months after initiation of prednisolone therapy, were assessed by conventional microscopic evaluation and computerized image analysis, and HMGB-1 expression was investigated by immunohistochemical staining. Muscle biopsy specimens from 7 healthy controls were also studied. RESULTS: Cytoplasmic HMGB-1 expression was detected in infiltrating rounded mononuclear cells, vascular endothelial cells, and muscle fibers of PM and DM patients. Extracellular staining surrounding the inflammatory cells was also observed. After treatment with high-dose prednisolone, cytoplasmic and extracellular HMGB-1 expression was significantly reduced, coinciding mainly with a decreased number of infiltrating inflammatory cells. Cytoplasmic HMGB-1 expression was still evident in endothelial cells and muscle fibers. No HMGB-1 expression was observed in muscle tissue from healthy controls. CONCLUSION: The cytoplasmic and extracellular distribution of HMGB-1 in muscle tissue may indicate an important role of this proinflammatory molecule in the pathogenesis of PM and DM. Furthermore, our findings indicate that systemically administered high-dose corticosteroids selectively down-regulate aberrant expression of HMGB-1 in mononuclear inflammatory cells in vivo.
Adult↗
Antiarthritic effect of bee venom: inhibition of inflammation mediator generation by suppression of NF-kappaB through interaction with the p50 subunit.
OBJECTIVE: To investigate the molecular mechanisms of the antiarthritic effects of bee venom (BV) and melittin (a major component of BV) in a murine macrophage cell line (Raw 264.7) and in synoviocytes obtained from patients with rheumatoid arthritis. METHODS: We evaluated the antiarthritic effects of BV in a rat model of carrageenan-induced acute edema in the paw and in a rat model of chronic adjuvant-induced arthritis. The inhibitory effects of BV and melittin on inflammatory gene expression were measured by Western blotting, and the generation of prostaglandin E(2) (PGE(2)) and nitric oxide (NO) and the intracellular calcium level were assayed. NF-kappaB DNA binding and transcriptional activity were determined by gel mobility shift assay or by luciferase assay. Direct binding of BV and melittin to the p50 subunit of NF-kappaB was determined with a surface plasmon resonance analyzer. RESULTS: BV (0.8 and 1.6 mug/kg) reduced the effects of carrageenan- and adjuvant-induced arthritis. This reducing effect was consistent with the inhibitory effects of BV (0.5, 1, and 5 mug/ml) and melittin (5 and 10 mug/ml) on lipopolysaccharide (LPS; 1 mug/ml)-induced expression of cyclooxygenase 2, cytosolic phospholipase A(2), inducible NO synthase, generation of PGE(2) and NO, and the intracellular calcium level. BV and melittin prevented LPS-induced transcriptional and DNA binding activity of NF-kappaB via the inhibition of IkappaB release and p50 translocation. BV (affinity [K(d)] = 4.6 x 10(-6)M) and melittin (K(d) = 1.2 x 10(-8)M) bound directly to p50. CONCLUSION: Target inactivation of NF-kappaB by directly binding to the p50 subunit is an important mechanism of the antiarthritic effects of BV.
Animals↗
[Effects of angiotensin II on inflammation mediators in healthy subjects].
BACKGROUND AND OBJECTIVE: Inflammatory reactions mediated by cytokines play a central role in the development of atherosclerotic vascular changes. Numerous experimental studies have suggested a connection between the renin-angiotensin-aldosterone system and cytokine liberation from endothelium. This study investigated the effect of exogenous angiotensin II on cytokine liberation in healthy subjects. METHODS: Nine healthy men, aged 25-28 years, having given informed consent, were given angiotensin II infusions of 1, 3 and 10 ng/kg/min, each time over 45 min, once with and once without preceding oral intake of an AT (1)-receptor antagonist (160 mg valsartan). Arterial blood pressures were measured oscillometrically every 5 min. Blood was taken at the end of each perfusion period and one each after its end, measurements being made of plasma activity of angiotensin II, aldosterone, and the pro-inflammatory cytokines tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and the vascular cell adhesion molecule (VCAM)-1. RESULTS: Plasma angiotensin II concentrations during perfusion rose from 14.7 +/- 16.5 pg/ml to 200.1 +/- 127.2 pg/ml (p< 0.001). The plasma concentrations of angiotensin II were again within the basal range (16.3 +/- 24.8 pg/ml) one hour after the end of perfusion. Angiotensin II raised the systolic and diastolic blood pressure from 121 +/- 9/70 +/- 6 mmHg to a maximum of 146 +/- 6/97 +/- 3 mmHg (p<0.001). This blood pressure rise was prevented by prior administration of the AT (1)-receptor antagonist. Neither the angiotensin II infusion nor the simultaneous administration of AT (1)-antagonist altered the circulating plasma level of TNF-alpha, IL-6 or VCAM-1. CONCLUSION: Increased circulating plasma levels of angiotensin II induce a significant rise in arterial pressure of healthy male subjects, but do not in the short therm produce a change in the plasma levels of the cytokines TNF-alpha, IL-6 and VCAM-1. These results in healthy subjects throw doubt on the hypothesis that, at least in the short term, the effect of angiotensin II on changes in those cytokines measured in this study are independent of the blood pressure.
Adult↗