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Intravascular hemolysis, in addition to reducing red cell counts, incurs extensive vascular inflammation and oxidative stress. One product of hemolysis, heme, is a potent danger associated molecular pattern (DAMP), activating leukocytes and inducing cytokine expression and processing, among other pro-inflammatory effects. We explored pathways by which heme-induced inflammation may be amplified under sterile conditions. Incubation of human Mϕs, differentiated from CD14 + cells, with heme induced time- and concentration-dependent gene and protein expression of S100A8, a myeloid cell-derived alarmin. Human Mϕ stimulation with recombinant S100A8, in turn, induced robust pro-IL-1β expression that was dependent upon NF-κB activation, gene transcription, and partially dependent upon TLR4-mediated signaling. Moreover, heme itself stimulated significant Mϕ pro-IL-1β gene and protein expression via an S100A8-mediated mechanism and greatly amplified S100A8-driven NLRP3 inflammasome-mediated IL-1β secretion. In vivo, induction of acute intravascular hemolysis in mice induced a rapid elevation of plasma S100A8 that could be abolished by hemopexin, a heme scavenger. Finally, plasma S100A8 levels were found to be significantly elevated in patients with the inherited hemolytic anemia, sickle cell anemia, when compared with levels in healthy individuals. In conclusion, we demonstrate that hemolytic processes are associated with S100A8 generation and that some of the inflammatory effects of heme may be amplified by autocrine S100A8 production. Findings suggest a mechanism by which hemolytic inflammation could be propagated via leukocyte priming by endogenous proteins, even in sterile inflammatory environments such as those that occur in the hemolytic diseases. S100A8 may represent a therapeutic target for reducing inflammation in hemolytic disorders., (©2019 Society for Leukocyte Biology.)

NOD-like receptor protein 3 (NLRP3) inflammasome activation triggers caspase-1 activation-induced maturation of interleukin (IL)-1β and IL-18 and therefore is important for the development of the host defense against various RNA viral diseases. However, the implication of this protein complex in human metapneumovirus (HMPV) disease has not been fully studied. Herein, we report that NLRP3 inflammasome plays a detrimental role during HMPV infection because NLRP3 inflammasome inhibition protected mice from mortality and reduced weight loss and inflammation without impacting viral replication. We also demonstrate that NLRP3 inflammasome exerts its deleterious effect via IL-1β production since we observed reduced mortality, weight loss and inflammation in IL-1β-deficient (IL-1β-/-) mice, as compared to wild-type animals during HMPV infection. Moreover, the effect on these evaluated parameters was not different in IL-1β-/- and wild-type mice treated with an NLRP3 inflammasome inhibitor. The production of IL-1β was also abrogated in bone marrow derived macrophages deficient for NLRP3. Finally, we show that small hydrophobic protein-deleted recombinant HMPV (HMPV ΔSH) failed to activate caspase-1, which is responsible for IL-1β cleavage and maturation. Furthermore, HMPV ΔSH-infected mice had less weight loss, showed no mortality and reduced inflammation, as compared to wild-type HMPV-infected mice. Thus, NLRP3 inflammasome activation seems to be triggered by HMPV SH protein in HMPV disease. In summary, once activated by the HMPV SH protein, NLRP3 inflammasome promotes the maturation of IL-1β, which exacerbates HMPV-induced inflammation. Therefore, the blockade of IL-1β production by using NLRP3 inflammasome inhibitors might be a novel potential strategy for the therapy and prevention of HMPV infection., Competing Interests: The authors have declared that no competing interests exist.

The role of macrophages during regeneration in zebrafish has been well-documented. Nevertheless, new evidence indicates that zebrafish macrophages are a heterogeneous population of cells, and that they can play different roles during immune responses and in tissue restoration after damage and infection. In this work, we first aimed to classify zebrafish macrophages according to their distribution in the larva during homeostasis and after tissue damage, distinguishing peripheral, and hematopoietic tissue resident macrophages. We discovered differences between the migratory behavior of these two macrophage populations both before and after tissue damage, triggered by the amputation of the tail fin. Further, we found a specific role for peripheral tissue-resident macrophages, and we propose that these cells contribute to tail fin regeneration by down-regulating inflammatory mediators such as interleukin-1b ( il1b ) and by diminishing reactive oxygen species (ROS) in the damage site. Our work suggests that specific macrophage populations recruited after tissue damage in zebrafish larvae can display different functions during both inflammation and tissue regeneration.

Mutations in Wiskott-Aldrich syndrome protein (WASP) cause autoimmune sequelae including colitis. Yet, how WASP mediates mucosal homeostasis is not fully understood. Here we show that WASP-mediated regulation of anti-inflammatory macrophages is critical for mucosal homeostasis and immune tolerance. The generation and function of anti-inflammatory macrophages are defective in both human and mice in the absence of WASP. Expression of WASP specifically in macrophages, but not in dendritic cells, is critical for regulation of colitis development. Importantly, transfer of WT anti-inflammatory macrophages prevents the development of colitis. DOCK8-deficient macrophages phenocopy the altered macrophage properties associated with WASP deficiency. Mechanistically, we show that both WASP and DOCK8 regulates macrophage function by modulating IL-10-dependent STAT3 phosphorylation. Overall, our study indicates that anti-inflammatory macrophage function and mucosal immune tolerance require both WASP and DOCK8, and that IL-10 signalling modulates a WASP-DOCK8 complex.

Interleukin-1 alpha (IL-1α) and beta (IL-1β) are pleiotropic cytokines affecting multiple cells and regulating many immune and inflammatory responses. The recent finding that nuclear IL-1α is recruited to sites of DNA damage, and its ability to actively sense and report genotoxic stress to the surrounding tissue, dramatically alters the way we view IL-1 biology. This discovery add a new face to the classical "danger theory" and show that danger signaling is not strictly limited to passive release or dying cells. Most importantly, as now physiological stresses are linked to the release or secretion of IL-1α, chronic danger signaling and the alarmin inhibition should be considered as a new therapeutic approach for many diseases that are characterized by ongoing DNA damage, stress signaling and inflammation., (Copyright © 2016. Published by Elsevier Ltd.)

Interleukin-1β is widely known as an inflammatory cytokine, and is an important and indispensable factor to understand inflammation. Therefore many researchers have investigated function and property of interleukin-1β. However some questions still remain to be fully elucidated. To approach these questions, bioimaging technology has been exploited recently. As interleukin-1β is regulated by unique mechanism via transcriptional activation and protein processing, several imaging tools have been developed for analyzing interleukin-1β by applying the regulatory mechanism. In this review I introduce representative interleukin-1β-related imaging technologies including basic principle of them and findings obtained with them. Additionally I referred briefly to other imaging technologies for monitoring inflammation in the last section.

Recently, glucagon-like peptide-1 (GLP-1) levels have been found to be increased in response to inflammatory stimuli, leading to insulin secretion and prevention of hyperglycaemia during endotoxemia in mice. In the present study, we assess the relevance of the other incretin hormone, glucose-dependent insulinotropic peptide (GIP), as a regulator of glucose metabolism under inflammatory conditions. We found that lipopolysaccharide (LPS) increased GIP secretion in a time- and dose-dependent manner in C57BL/6J mice. To elucidate the underlying mechanisms, mice were injected with inflammatory cytokines known to be released by LPS. Circulating GIP levels significantly increased in response to interleukin (IL)-1β but not IL-6 or tumour necrosis factor (TNF)-α administration. Using respective knockout mice we found that LPS-mediated GIP secretion was selectively dependent on IL-1 signalling. To evaluate the functional relevance of inflammatory GIP secretion we pretreated mice with the GIP-receptor antagonist (Pro3)GIP. This blunted LPS-induced TNF-α and IL-6 secretion but did not affect LPS-induced insulin secretion or blood glucose-lowering. In conclusion, GIP provides a novel link between the immune system and the gut, with proinflammatory-immune modulatory function but minor glucose regulatory relevance in the context of acute endotoxemia., (© 2016 John Wiley & Sons Ltd.)

Expression of interleukin-6 (IL-6) upon acute inflammatory stress is significantly augmented by aging in adipose tissue, a major source of this cytokine. In the present study, we examined the mechanism of age-dependent IL-6 overproduction using visceral white adipose tissue from C57BL/6 mice. Upon treatment with lipopolysaccharide (LPS) in vitro, IL-6 was produced by adipose tissue explants, and secreted levels were significantly higher in cultures from aged (24 months) mice compared to young (4 months). Interleukin 1 beta (IL-1β) and tumor necrosis factor alpha (TNFα), two inducers of IL-6, were mainly produced by the lungs and spleen rather than adipose tissue in mice after LPS injection. Treatment of adipose explants with physiological levels of IL-1β induced significant age-dependent secretion of IL-6, while treatment with TNFα had little effect, demonstrating an augmented response of adipose tissues to IL-1β in the aged. In vitro experiments utilizing a neutralizing antibody against IL-1β and in vivo experiments utilizing IL-1-receptor-1 deficient mice, confirmed that IL-6 overproduction in the aged is regulated by autocrine/paracrine action of IL-1β which specifically occurs in aged adipose tissues. These findings indicate an elevated inflammatory potential of adipose tissue in the aged and a unique IL-1β-mediated mechanism for IL-6 overproduction, which may impact age-associated vulnerability to acute inflammatory diseases such as sepsis., (© The Author 2014. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Osteoarthritis (OA) is an age-related joint disease that is characterized by the degeneration of articular chondrocytes. Nuclear enzyme poly(ADP-ribose) polymerase 1 (PARP-1) is associated with inflammation response. We investigated the role of PARP-1 in interleukin-1β (IL-1β)-stimulated human articular chondrocytes and its underlying mechanism. Cell viability and apoptosis were evaluated by using 3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazoliumromide assay and flow cytometry, respectively. Tumor necrosis factor-α (TNF-α) level was measured by enzyme-linked immunosorbent assay. The mRNA and protein expression levels of PARP-1, IL-1 receptor (IL-1R), inducible nitric oxide synthase (iNOS), matrix metalloproteinases (MMPs), and tissue inhibitor of metalloproteinases-1 (TIMP-1) were determined by real-time reverse transcriptase-polymerase chain reaction and western blot analysis, respectively. The expression and phosphorylation of NF-кB p65 were measured by western blot analysis. Results showed that stimulation of chondrocytes with IL-1β caused a significant up-regulation of PARP-1 and IL-1R, resulting in NF-кB p65 nuclear translocation and phosphorylation associated with an increase of TNF-α secretion and iNOS expression. PARP-1 was inhibited by siRNA transfection. Results showed that PARP-1 inhibition suppressed IL-1β-induced reduction of cell viability and up-regulation of cell apoptosis, with a reduced IL-1R expression. PARP-1 inhibition also effectively reversed IL-1β-induced inflammatory response through inhibiting the IL-1R/NF-кB pathway. These data suggested that PARP-1 inhibition prevents IL-1β-induced inflammation response at least partly by inhibiting the IL-1R/NF-кB signaling pathway in human articular chondrocytes. Moreover, PARP-1 inhibition reduced MMPs expression and increased TIMP-1 expression, suggesting that PARP-1 inhibition could suppress cartilage destruction by modulating the balance between MMPs and TIMP-1. Inhibition of PARP-1 might be useful in the treatment of OA., (© The Author 2015. Published by ABBS Editorial Office in association with Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences.)

Caspase-8 is an initiator and apical activator caspase that plays a central role in apoptosis. Caspase-8-deficient mice are embryonic lethal, which makes study of caspase-8 in primary immune cells difficult. Recent advances have rescued caspase-8-deficient mice by crossing them to mice deficient in receptor-interacting serine-threonine kinase 3 (RIPK3). These genetic tools have made it possible to study the role of caspase-8 in vivo and in primary immune cells. Several recent studies have identified novel roles for caspase-8 in modulating IL-1β and inflammation, showing that caspase-8 directly regulates IL-1β independent of inflammasomes or indirectly through the regulation of inflammasomes, depending on the stimulus or stimuli that initiate the signaling cascade. Here, we address recent findings on caspase-8 and its role in modulating IL-1β and inflammation., (Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

M2 macrophages suppress inflammation in numerous disorders, including tumour formation, infection and obesity. However, the exact role of M2 macrophages in the context of several other diseases is still largely undefined. We here show that human M2 macrophages promote inflammation instead of suppressing inflammation on simultaneous exposure to complexed IgG (c-IgG) and TLR ligands, as occurs in the context of diseases such as rheumatoid arthritis (RA). c-IgG-TLR ligand co-stimulation of M2 macrophages selectively amplifies production of pro-inflammatory cytokines TNF-α, IL-1β and IL-6 and promotes Th17 responses, which all play a critical role in RA pathology. Induction of pro-inflammatory cytokines on c-IgG co-stimulation mainly depends on Fc gamma receptor IIa (FcγRIIa), which selectively amplifies cytokine gene transcription and induces caspase-1 activation. These data indicate that FcγR-TLR cross-talk may be targeted for treatment to attenuate inflammation in RA, by restoring the anti-inflammatory function of M2 macrophages.

Objective: Interleukin 1 Receptor 1 (IL1R1) and its ligand, IL1β, are upregulated in cardiovascular disease, obesity, and infection. Previously, we reported a higher level of IL1R1 transcripts in platelets from obese individuals of the Framingham Heart Study (FHS), but its functional effect in platelets has never been described. Additionally, IL1β levels are increased in atherosclerotic plaques and in bacterial infections. The aim of this work is to determine whether IL1β, through IL1R1, can activate platelets and megakaryocytes to promote atherothrombosis., Approach and Results: We found that IL1β-related genes from platelets, as measured in 1819 FHS participants, were associated with increased body mass index, and a direct relationship was shown in wild-type mice fed a high-fat diet. Mechanistically, IL1β activated nuclear factor-κB and mitogen-activated protein kinase signaling pathways in megakaryocytes. IL1β, through IL1R1, increased ploidy of megakaryocytes to 64+ N by 2-fold over control. IL1β increased agonist-induced platelet aggregation by 1.2-fold with thrombin and 4.2-fold with collagen. IL1β increased adhesion to both collagen and fibrinogen, and heterotypic aggregation by 1.9-fold over resting. High fat diet-enhanced platelet adhesion was absent in IL1R1(-/-) mice. Wild-type mice infected with Porphyromonas gingivalis had circulating heterotypic aggregates (1.5-fold more than control at 24 hours and 6.2-fold more at 6 weeks) that were absent in infected IL1R1(-/-) and IL1β(-/-) mice., Conclusions: In summary, IL1R1- and IL1β-related transcripts are elevated in the setting of obesity. IL1R1/IL1β augment both megakaryocyte and platelet functions, thereby promoting a prothrombotic environment during infection and obesity; potentially contributing to the development of atherothrombotic disease.

Necrotic cell death alerts the acquired immune system to activate naïve T cells even in the absence of non-self derived molecules (e.g. pathogens). In addition, sterile necrosis leads to innate immune-mediated acute inflammation. The dying cells still represent a threat to the body that should be eliminated by the host immune response. Although the inflammatory response plays important roles in protecting the host and repairing tissues, it can also cause the collateral damage to normal tissues that underlies disease pathogenesis. Tissue resident macrophages recognize the danger signals released from necrotic cells via the pattern recognition receptors and secrete IL-1 that results in acute neutrophilic inflammation. This article will review our current knowledge especially focusing on the role of IL-1 in the sterile necrotic cell death induced inflammation., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objectives: Annexin A5 is a 35-kDa protein with high affinity binding to negatively charged phospholipids. However, its effects on sepsis are not known. Our aim was to study the effects of annexin A5 on myocardial tumor necrosis factor-α expression, cardiac function, and animal survival in endotoxemia., Design: Prospective experimental study., Setting: University laboratory., Subjects: Adult male C57BL/6 mice., Interventions: Mice were challenged with lipopolysaccharide (4 or 20 mg/kg, i.p.) to induce endotoxemia with and without recombinant human annexin A5 treatment (5 or 10 μg/kg, i.v.). Cytokine expression and cardiac function were assessed, and animal survival was monitored., Measurements and Main Results: Treatment with annexin A5 inhibited myocardial mitogen-activated protein kinase, and nuclear factor-κB activation in mice with endotoxemia. Furthermore, annexin A5-treated animals showed significant reductions in myocardial and plasma levels of tumor necrosis factor-α and interleukin-1β while cardiac function was significantly improved during endotoxemia. Additionally, 5-day animal survival was significantly improved by either an immediate or a 4-hour delayed annexin A5 treatment after lipopolysaccharide challenge. Importantly, annexin A5 dose-dependently inhibited lipopolysaccharide binding to a toll-like receptor-4/myeloid differentiation factor 2 fusion protein., Conclusions: Annexin A5 treatment decreases cytokine expression and improves cardiac function and survival during endotoxemia. These effects of annexin A5 are mediated by its ability to inhibit lipopolysaccharide binding to toll-like receptor-4, leading to reductions in mitogen-activated protein kinase and Akt signaling. Our study suggests that annexin A5 may have therapeutic potential in the treatment of sepsis.

Background: The fat mass and obesity associated gene (FTO) is widely investigated in humans regarding its important roles in obesity and type 2 diabetes. Studies in mammals demonstrate that FTO is also associated with inflammation markers. However, the association of FTO with inflammation in chickens remains unclear. In this study, male chickens on day 28 posthatching were injected intraperitoneally with lipopolysaccharide (LPS) or saline to investigate whether the FTO gene is involved in LPS-induced inflammation., Results: We detected significant down-regulation of FTO mRNA in the liver (P < 0.01), but not in the hypothalamus, 2 and 24 h after LPS challenge. Toll-like receptor (TLR) 2 (P < 0.01) and TLR4 (P < 0.01) followed the same pattern as FTO, being suppressed significantly in liver but not in hypothalamus. IL-1β was dramatically up-regulated (P < 0.01) in both liver and hypothalamus 2 h after LPS challenge, while activation of IL-6 was observed in the liver (P < 0.01), but not in hypothalamus. The 5'-flanking sequence of the chicken FTO gene contains nine predicted binding sites for CCAAT/enhancer binding protein beta (C/EBP beta) and one for signal transducer and activator of transcription 3 (STAT3). Significant elevation of C/EBP beta was detected in the liver (P < 0.01), but not in the hypothalamus, 2 h after LPS challenge. Lipopolysaccharide challenge increased the C/EBP beta binding to FTO promoter in the liver (P < 0.01 for fragment 1, P < 0.05 for fragment 2), although the protein content of C/EBP beta was not altered. Moreover, injection of LPS resulted in enhanced phosphorylation of liver STAT3, a downstream transcription factor in IL-6 signaling. Although phosphorylated STAT3 was not detected to directly bind to FTO promoter, it was found to interact with C/EBP beta., Conclusion: Our results reveal that FTO expression in liver, but not in hypothalamus, is affected by the i.p. injection of LPS, which may be mediated through tissue-specific FTO transcriptional regulation by C/EBP beta and STAT3 interaction.

Study Objectives: Childhood obstructive sleep apnea syndrome (OSAS) is associated with an elevation of inflammatory markers such as C-reactive protein (CRP) that correlates with specific morbidities and subsides following intervention. In adults, OSAS is associated with activation of the transcription factor nuclear factor kappa B (NF-kB). We explored the mechanisms underlying NF-kB activation, based on the hypothesis that specific NF-kB signaling is activated in children with OSAS., Design: Adenoid and tonsillar tissues from children with OSAS and matched controls were immunostained against NF-kB classical (p65 and p50) and alternative (RelB and p52) pathway subunits, and NF-kB-dependent cytokines: interleukin (IL)- 1α, IL-1β, tumor necrosis factor-α, and IL-8). Serum CRP levels were measured in all subjects. NF-kB induction was evaluated by a luciferase-NF-kB reporter assay in L428 cells constitutively expressing NF-kB and in Jurkat cells with inducible NF-kB expression. p65 translocation to the nucleus, reflecting NF-kB activation, was measured in cells expressing fluorescent NF-kB-p65-GFP (green fluorescent protein)., Setting: Sleep research laboratory., Patients or Participants: Twenty-five children with OSAS and 24 without OSAS., Interventions: N/A., Measurements and Results: Higher expression of IL-1α and classical NF-kB subunits p65 and p50 was observed in adenoids and tonsils of children with OSAS. Patient serum induced NF-kB activity, as measured by a luciferase-NF-kB reporter assay and by induction of p65 nuclear translocation in cells permanently transfected with GFP-p65 plasmid. IL-1β showed increased epithelial expression in OSAS tissues., Conclusions: Nuclear factor kappa B is locally and systemically activated in children with obstructive sleep apnea syndrome. This observation may motivate the search for new anti-inflammatory strategies for controlling nuclear factor kappa B activation in obstructive sleep apnea syndrome.

Objective: Innate and adaptive immunity may contribute to gland dysfunction in patients with primary Sjögren's syndrome (pSS). The P2X7 receptor (P2X7 R)-NLRP3 inflammasome complex modulates the release of the inflammatory cytokines IL-1β and IL-18. The presence of P2X7 R in salivary glands suggests an interesting scenario for the initiation and amplification of the innate immune response in pSS. Therefore, the aim of this study was to assess the role of the P2X7 R-NLRP3 inflammasome in pSS., Subjects and Methods: Twenty-one consecutive patients with pSS according to the American-European Consensus Group criteria and 15 patients with sicca syndrome (i.e. without Sjögren's syndrome, non-SS) were enrolled in this study, together with six control (CTL) subjects. Expression of the P2X7R-NLRP3 platform and IL-18 was determined by real-time PCR and western blotting in gland specimens and peripheral lymphomonocytes; data were related to patients\x92 clinical, serological and histopathological characteristics. The presence of IL-18 was determined in gland and saliva samples., Results: P2X7 R expression was significantly higher in salivary glands from individuals with pSS than in those from non-SS and CTL subjects. Accordingly, the gene expression levels of the inflammasome components NLRP3, ASC and caspase-1 were significantly higher in pSS gland specimens, and this was paralleled by an increased expression of mature IL-18 in pSS saliva samples. The expression of both the P2X7 R and the inflammasome components was a marker of disease-related glandular involvement, being increased in patients with anti-Ro/SSA positivity and correlated with focus score., Conclusion: The results of this study suggest an involvement of the P2X7 R-inflammasome-caspase-1-IL-18 axis in the development of pSS exocrinopathy. This finding provides the basis for studying the complex mechanisms underlying pSS, as well as for developing novel potential therapeutic strategies., (© 2013 The Association for the Publication of the Journal of Internal Medicine.)

Microglia are the resident macrophages of the CNS, which secrete several pro- and anti-inflammatory cyto-chemokines including interleukin-1β (IL-1β), in response to pathogenic stimuli. Once secreted, IL-1β binds to IL-1 receptor present on microglia and initiates the production of inflammatory cytokines in microglia. However, the detailed information regarding the molecular mechanisms of IL-1β triggered inflammatory pathways in microglia is lacking. Our studies focused on the role of Krüppel-like factor 4 (Klf4) in mediating the regulation of pro-inflammatory gene expression upon IL-1β stimulation in microglia. Our studies show that stimulation of microglia with IL-1β robustly induces Klf4 via PI3K/Akt pathway which positively regulates the production of endogenous IL-1β as well as other pro-inflammatory markers, cyclooxygenase-2, monocyte chemoattractant protein-1 and interleukin-6 (IL-6). In addition, we report that Klf4 negatively regulates the expression of inducible nitric oxide synthase, thereby playing a key role in regulating the immunomodulatory activities of microglia., (© 2013 International Society for Neurochemistry.)

Purpose of Review: Cancer patients undergoing treatment with cytotoxic chemotherapeutic agents (CCAs) often experience a cluster of treatment-related symptoms, which include fatigue, loss of appetite, disturbed sleep, depressed mood, cognitive difficulties, and changes in body composition. This symptom cluster collectively referred to herein as cancer treatment-related symptoms (CTRSs) decrease quality of life, and physical and social functioning. The preclinical and clinical studies described in this review represent important progress in understanding potential underlying mechanisms of CTRS., Recent Findings: Recent studies support a role for CCA-induced interleukin-1β (IL-1β) signaling in the cause of CTRS. CCAs may share a common ability to activate intracellular stress response pathways to trigger the synthesis, processing, and release of IL-1β from immune cells. Fatigue, sleep disturbance, and cognitive difficulties in cancer patients exposed to CCAs correlate with plasma levels of IL-6, IL-1 receptor antagonist, and soluble tumor necrosis factor receptor-I/II, surrogate markers of IL-1β-mediated central nervous system (CNS) inflammation. Additional preclinical work suggests IL-1β-mediated CNS inflammation may cause CTRS by altering hypothalamic and hippocampal functioning., Summary: Although additional research is necessary to further establish the link between CCA exposure, IL-1β-mediated inflammatory processes and CTRS, these data provide hints for future studies and therapeutic approaches in ameliorating these symptoms in cancer patients.

Early life experiences, such as prenatal stress, may result in permanent alterations in the function of the nervous and immune systems. In this study we have assessed whether prenatal stress affects the inflammatory response of the hippocampal formation of male mice to an inflammatory challenge during adulthood. Pregnant C57BL/6 mice were randomly assigned to stress (n=10) or non-stress (n=10) groups. Animals of the stress group were placed in plastic transparent cylinders and exposed to bright light for 3 sessions of 45min every day from gestational day 12 to parturition. Non-stressed pregnant mice were left undisturbed. At four months of age, non stressed and prenatally stressed male offspring were killed, 24h after the systemic administration of lipopolysaccharide (LPS) or vehicle. Under basal conditions, prenatally stressed animals showed increased expression of interleukin 1β and tumor necrosis factor-α (TNF-α) in the hippocampus and an increased percentage of microglia cells with reactive morphology in CA1 compared to non-stressed males. Furthermore, prenatally stressed mice showed increased TNF-α immunoreactivity in CA1 and increased number of Iba-1 immunoreactive microglia and GFAP-immunoreactive astrocytes in the dentate gyrus after LPS administration. In contrast, LPS did not induce such changes in non-stressed animals. These findings indicate that prenatal stress induces a basal proinflammatory status in the hippocampal formation during adulthood that results in an enhanced activation of microglia and astrocytes in response to a proinflammatory insult., (Copyright © 2012 Elsevier Inc. All rights reserved.)

It has been recently demonstrated that interleukin 1β (IL-1β) plays a central role in monosodium urate crystal-induced inflammation and that the NALP3 inflammasome plays a major role in IL-1β production. These discoveries have offered new insights into the pathogenesis of acute gouty arthritis. In this review, we discuss the molecular mechanisms by which monosodium urate crystals induce acute inflammation and examine the mechanisms of action (MOAs) of traditional anti-inflammatory drugs (e.g., nonsteroidal anti-inflammatory drugs, colchicine, and glucocorticoids) and biologic agents (e.g., the IL-1β antagonists anakinra, rilonacept, and canakinumab) to understand how their MOAs contribute to their safety profiles. Traditional anti-inflammatory agents may act on the IL-1β pathway at some level; however, their MOAs are broad-ranging, unspecific, and biologically complex. This lack of specificity may explain the range of systemic adverse effects associated with them. The therapeutic margins of nonsteroidal anti-inflammatory drugs, colchicine, and glucocorticoids are particularly low in elderly patients and in patients with cardiovascular, metabolic, or renal comorbidities that are frequently associated with gouty arthritis. In contrast, the IL-1β antagonists act on very specific targets of inflammation, which may decrease the potential for systemic adverse effects, although infrequent but serious adverse events (including infection and administration reactions) have been reported. Because these IL-1β antagonists target an early event immediately downstream from NALP3 inflammasome activation, they may provide effective alternatives to traditional agents with minimal systemic adverse effects. Results of ongoing trials of IL-1β antagonists will likely provide clarification of their potential role in the management of acute gouty arthritis.

Interleukin-1β (IL-1β) is considered to be one of the most important mediators in the pathogenesis of inflammatory diseases, particularly in neurodegenerative diseases such as multiple sclerosis (MS). MS is a chronic inflammatory disease characterized by demyelination and remyelination events, with unpredictable relapsing and remitting episodes that seldom worsen MS lesions. We proposed to study the effect of a unique component of the inflammatory process, IL-1β, and evaluate its effect in repeated episodes, similar to the relapsing-remitting MS pathology. Using adenoviral vectors, we developed a model of focal demyelination/remyelination triggered by the chronic expression of IL-1β. The long-term expression of IL-1β in the striatum produced blood-brain barrier (BBB) breakdown, demyelination, microglial/macrophage activation, and neutrophil infiltration but no overt neuronal degeneration. This demyelinating process was followed by complete remyelination of the area. This simple model allows us to study demyelination and remyelination independently of the autoimmune and adaptive immune components. Re-exposure to this cytokine when the first inflammatory response was still unresolved generated a lesion with decreased neuroinflammation, demyelination, axonal injury and glial response. However, a second long-term expression of IL-1β when the first lesion was resolved could not be differentiated from the first event. In this study, we demonstrated that the response to a second inflammatory stimulus varies depending on whether the initial lesion is still active or has been resolved. Considering that anti-inflammatory treatments have shown little improvement in MS patients, studies about the behavior of specific components of the inflammatory process should be taken into account to develop new therapeutic tools., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Tumor-associated macrophages promote tumor growth by stimulating angiogenesis and suppressing antitumor immunity. Thus, therapeutics that inhibit macrophage recruitment to tumors may provide new avenues for cancer therapy. In this study, we showed how chemoattractants stromal cell-derived growth factor 1 alpha (SDF-1α) and interleukin 1 beta (IL-1β) collaborate with myeloid cell integrin-α4β1 to promote tumor inflammation and growth. We found that SDF-1α and IL-1β are highly expressed in the microenvironments of murine lung, pancreatic, and breast tumors; surprisingly, SDF-1α was expressed only by tumor cells, whereas IL-1β was produced only by tumor-derived granulocytes and macrophages. In vivo, both factors directly recruited proangiogenic macrophages to tissues, whereas antagonists of both factors suppressed tumor inflammation, angiogenesis, and growth. Signals induced by IL-1β and SDF-1α promoted the interaction of talin and paxillin with the cytoplasmic tails of integrin-α4β1, thereby stimulating myeloid cell adhesion to endothelium in vitro and in vivo. Inhibition of integrin-α4β1, SDF-1α, or IL-1β was sufficient to block tumor inflammation and growth, and the combined blockade of these molecules greatly accentuated these effects. Furthermore, antagonists of integrin-α4β1 inhibited chemotherapy-induced tumor inflammation and acted synergistically with chemotherapeutic agents to suppress tumor inflammation and growth. These results show that targeting myeloid cell recruitment mechanisms can be an effective approach to suppress tumor progression., (©2011 AACR)

Purpose of Review: The systemic inflammatory response to injury is essential for wound healing and recovery in concert with other endocrinological, metabolic and immunological changes. However, recent studies suggest that a hyperinflammatory state is associated with adverse perioperative outcomes. Therefore interventions that modulate the inflammatory response, surgical, anaesthetic and pharmacological, may enhance recovery with fewer complications., Recent Findings: Basic research on wound biology has shown the importance of genetic variability in determining the initial inflammatory response. Clinically, studies of cardiac surgery predominate in which genetic polymorphisms have been shown to result in a hyperinflammatory state., Summary: The use of an interleukin-1 receptor antagonist to control wound pain and limit local inflammation is under consideration. The role of glucocorticoids in obtunding the inflammatory response to injury with improved outcome requires confirmation with better-quality trials. Systemic lidocaine is anti-inflammatory but is effective only in abdominal surgery. NSAIDs are neglected, despite their widespread clinical use and merit detailed investigation.

Angiotensin II is implicated in cardiovascular diseases, which is associated with a role in increasing vascular inflammation. The present study investigated how angiotensin II modulates vascular inflammatory signaling and expression of inducible nitric oxide synthase (iNOS) and vascular cell adhesion molecule (VCAM)-1. In cultured rat aortic vascular smooth muscle cells (VSMCs), angiotensin II suppressed interleukin-1β-induced prolonged phosphorylation of extracellular signal-regulated kinase (ERK) and ribosomal S6 kinase (RSK)-1, and nuclear translocation of nuclear factor (NF)-κB, leading to decreased iNOS but enhanced VCAM-1 expression, associated with an up-regulation of mitogen-activated protein kinase phosphatase-1 expression. Knock-down of RSK1 selectively down regulated interleukin-1β-induced iNOS expression without influencing VCAM-1 expression. In vivo experiments showed that interleukin-1β, iNOS, and VCAM-1 expression were detectable in the aortic arches of both wild-type and apolipoprotein E-deficient (ApoE(-/-)) mice. VCAM-1 and iNOS expression were higher in ApoE(-/-) than in wild type mouse aortic arches. Angiotensin II infusion (3.2 mg/kg/day, for 6 days, via subcutaneous osmotic pump) in ApoE(-/-) mice enhanced endothelial and adventitial VCAM-1 and iNOS expression, but reduced medial smooth muscle iNOS expression associated with reduced phosphorylation of ERK and RSK-1. These results indicate that angiotensin II can differentially modulate inflammatory gene expression in aortic smooth muscle cells through influencing ERK-NF-κB crosstalk, which may contribute to angiotensin II-induced inflammatory disorders related to cardiovascular diseases., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The recognition of pathogen-derived molecules by the innate immune system is mediated by a number of receptors, including members of the TLR (Toll-like receptor), RLH [RIG (retinoic acid-inducible gene)-like helicase] and the NLR (NOD-like receptor) families. NLRs in particular are also involved in the recognition of host-derived 'danger'-associated molecules which are produced under conditions of cellular stress or injury. Activation of these receptors leads to the assembly of high-molecular-mass complexes called inflammasomes which in turn leads to the generation of active caspase 1 and to the production of mature IL-1β (interleukin 1β). The discovery that NLRP3 (NLR-related protein 3) can recognize host-derived particulate matter such as uric acid and cholesterol crystals has led to this inflammasome being implicated in a number of inflammatory diseases, including gout, atherosclerosis and Type 2 diabetes. In addition, aberrant NLRP3 activation has also been observed in a number of heritable disorders now referred to as cryopyrinopathies. On the other hand, a number of studies have reported that recognition of both viral and bacterial products by NLRs is required for effective pathogen clearance. The present review discusses both aspects of NLR activation and will highlight the role of additional inflammasome complexes in sensing infection.

The emergence of chronic inflammation during obesity in the absence of overt infection or well-defined autoimmune processes is a puzzling phenomenon. The Nod-like receptor (NLR) family of innate immune cell sensors, such as the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (Nlrp3, but also known as Nalp3 or cryopyrin) inflammasome are implicated in recognizing certain nonmicrobial originated 'danger signals' leading to caspase-1 activation and subsequent interleukin-1β (IL-1β) and IL-18 secretion. We show that calorie restriction and exercise-mediated weight loss in obese individuals with type 2 diabetes is associated with a reduction in adipose tissue expression of Nlrp3 as well as with decreased inflammation and improved insulin sensitivity. We further found that the Nlrp3 inflammasome senses lipotoxicity-associated increases in intracellular ceramide to induce caspase-1 cleavage in macrophages and adipose tissue. Ablation of Nlrp3 in mice prevents obesity-induced inflammasome activation in fat depots and liver as well as enhances insulin signaling. Furthermore, elimination of Nlrp3 in obese mice reduces IL-18 and adipose tissue interferon-γ (IFN-γ) expression, increases naive T cell numbers and reduces effector T cell numbers in adipose tissue. Collectively, these data establish that the Nlrp3 inflammasome senses obesity-associated danger signals and contributes to obesity-induced inflammation and insulin resistance.

Management of Graves' orbitopathy (GO) is challenging, as no reliable, specific, and safe medical therapeutic agents have yet been developed. We investigated the effect of quercetin in primary cultured orbital fibroblasts from GO, targeting pathways of inflammation, aberrant accumulation of extracellular matrix macromolecules, and adipose tissue expansion. Quercetin significantly attenuated intercellular adhesion molecule-1 (ICAM-1), interleukin (IL) -6, IL-8, and cyclooxygenase (COX) -2 mRNA expression, and inhibited IL-1β-induced increases in ICAM-1, IL-6, and IL-8 mRNA. Increased hyaluronan production induced by IL-1β or tumor necrosis factor-α was suppressed by quercetin in a dose- and time-dependent manner. Treatment with noncytotoxic doses of quercetin inhibited accumulation of intracytoplasmic lipid droplets and resulted in a dose-dependent decrease in expression of peroxisome proliferator-activated receptor γ, CCAAT/enhancer-binding protein (C/EBP) α, and C/EBPβ proteins. In conclusion, inhibition of inflammation, hyaluronan production, and adipogenesis by the natural plant product quercetin in vitro provides the basis for further study of its potential use in the treatment of GO.

Objective: Macrophages play an important role in the pathogenesis of insulin resistance via the production of proinflammatory cytokines. Our goal is to decipher the molecular linkage between proinflammatory cytokine production and insulin resistance in macrophages., Research Design and Methods: We determined cytokine profiles in cultured macrophages and identified interleukin (IL)-1β gene as a potential target of FoxO1, a key transcription factor that mediates insulin action on gene expression. We studied the mechanism by which FoxO1 mediates insulin-dependent regulation of IL-1β expression in cultured macrophages and correlated FoxO1 activity in peritoneal macrophages with IL-1β production profiles in mice with low-grade inflammation or insulin resistance., Results: FoxO1 selectively promoted IL-1β production in cultured macrophages. This effect correlated with the ability of FoxO1 to bind and enhance IL-1β promoter activity. Mutations of the FoxO1 binding site within the IL-1β promoter abolished FoxO1 induction of IL-1β expression. Macrophages from insulin-resistant obese db/db mice or lipopolysaccharide-inflicted mice were associated with increased FoxO1 production, correlating with elevated levels of IL-1β mRNA in macrophages and IL-1 protein in plasma. In nonstimulated macrophages, FoxO1 remained inert with benign effects on IL-1β expression. In response to inflammatory stimuli, FoxO1 activity was augmented because of an impaired ability of insulin to phosphorylate FoxO1 and promote its nuclear exclusion. This effect along with nuclear factor-κB acted to stimulate IL-1β production in activated macrophages., Conclusions: FoxO1 signaling through nuclear factor-κB plays an important role in coupling proinflammatory cytokine production to insulin resistance in obesity and diabetes.

Nucleotide-binding and oligomerization domain 2 (NOD2) belongs to the emerging Nod-like receptor (NLR) family considered important in innate immunity. Mutations in NOD2 cause Blau syndrome, an inherited inflammation of eye, joints, and skin. Mutations in a homologous region of another NLR member, NALP3, cause autoinflammation, wherein IL-1beta plays a critical role. Here, we tested the hypothesis that IL-1beta is a downstream mediator of NOD2-dependent ocular inflammation. We used a mouse model of NOD2-dependent ocular inflammation induced by muramyl dipeptide (MDP), the minimal bacterial motif sensed by NOD2. We report that MDP-induced ocular inflammation generates IL-1beta and IL-18 within the eye in a NOD2- and caspase-1-dependent manner. Surprisingly, two critical measures of ocular inflammation, leukocyte rolling and leukocyte intravascular adherence, appear to be completely independent of IL-1 signaling effects, as caspase-1 and IL-1R1-deficient mice still developed ocular inflammation in response to MDP. In contrast to the eye, a diminished neutrophil response was observed in an in vivo model of MDP-induced peritonitis in caspase-1-deficient mice, suggesting that IL-1beta is not essential in NOD2-dependent ocular inflammation, but it is involved, in part, in systemic inflammation triggered by NOD2 activation. This disparity may be influenced by IL-1R antagonist (IL-1Ra), as we observed differential IL-1Ra levels in the eye versus plasma at baseline levels and in response to MDP treatment. This report reveals a new in vivo function of NOD2 within the eye yet importantly, distinguishes NOD2-dependent from NALP3-dependent inflammation, as ocular inflammation in mice occurred independently of IL-1beta.

Background: Traumatic brain injury (TBI) with its associated morbidity is a major area of unmet medical need that lacks effective therapies. TBI initiates a neuroinflammatory cascade characterized by activation of astrocytes and microglia, and increased production of immune mediators including proinflammatory cytokines and chemokines. This inflammatory response contributes both to the acute pathologic processes following TBI including cerebral edema, in addition to longer-term neuronal damage and cognitive impairment. However, activated glia also play a neuroprotective and reparative role in recovery from injury. Thus, potential therapeutic strategies targeting the neuroinflammatory cascade must use careful dosing considerations, such as amount of drug and timing of administration post injury, in order not to interfere with the reparative contribution of activated glia., Methods: We tested the hypothesis that attenuation of the acute increase in proinflammatory cytokines and chemokines following TBI would decrease neurologic injury and improve functional neurologic outcome. We used the small molecule experimental therapeutic, Minozac (Mzc), to suppress TBI-induced up-regulation of glial activation and proinflammatory cytokines back towards basal levels. Mzc was administered in a clinically relevant time window post-injury in a murine closed-skull, cortical impact model of TBI. Mzc effects on the acute increase in brain cytokine and chemokine levels were measured as well as the effect on neuronal injury and neurobehavioral function., Results: Administration of Mzc (5 mg/kg) at 3 h and 9 h post-TBI attenuates the acute increase in proinflammatory cytokine and chemokine levels, reduces astrocyte activation, and the longer term neurologic injury, and neurobehavioral deficits measured by Y maze performance over a 28-day recovery period. Mzc-treated animals also have no significant increase in brain water content (edema), a major cause of the neurologic morbidity associated with TBI., Conclusion: These results support the hypothesis that proinflammatory cytokines contribute to a glial activation cycle that produces neuronal dysfunction or injury following TBI. The improvement in long-term functional neurologic outcome following suppression of cytokine upregulation in a clinically relevant therapeutic window indicates that selective targeting of neuroinflammation may lead to novel therapies for the major neurologic morbidities resulting from head injury, and indicates the potential of Mzc as a future therapeutic for TBI.

The incidence of type 2 diabetes (T2D) is rapidly expanding. Some of the more obvious pathologies associated with it include: defective glucose metabolism, obesity, cardiovascular disease and an inability to mount an effective immune response to infection by certain pathogenic organisms, leading to sepsis and death. A common tie linking these seemingly disparate complications is chronic inflammation. Today we know that inflammation is regulated locally and systemically by numerous biochemical signals. One of the most important of these signals is a class of molecules called cytokines. Cytokines can be generally classified as proinflammatory or anti-inflammatory and allow an organism to respond rapidly to an immune challenge by coordinating an appropriate immune response. In T2D, the balance between proinflammatory and anti-inflammatory cytokines is shifted toward proinflammation, potentially causing or exacerbating the health complications found in T2D. Over-nutrition has been shown to trigger the innate immune system but activation of the innate immune system, itself, induces hyperglycemia and insulin resistance. In all likelihood, diabetes and chronic inflammation are inseparable and act as a reciprocal feed-forward loop.

Decreases in both mass and secretory function of insulin-producing beta-cells contribute to the pathophysiology of type 2 diabetes. The histology of islets from patients with type 2 diabetes displays an inflammatory process characterized by the presence of cytokines, apoptotic cells, immune cell infiltration, amyloid deposits, and eventually fibrosis. This inflammatory process is probably the combined consequence of dyslipidemia, hyperglycemia, and increased circulating adipokines. Therefore, modulation of intra-islet inflammatory mediators, in particular interleukin-1 beta, appears as a promising therapeutic approach.

Many human diseases have been linked to inflammation, which is mediated by a number of chemical molecules including lipid mediators and cytokines. Polyunsaturated fatty acids (omega-6 and omega-3 fatty acids) are the precursors of the lipid mediators and play an important role in regulation of inflammation. Generally, omega-6 fatty acids (e.g. arachidonic acid) promote inflammation whereas omega-3 fatty acids (e.g. eicosapentaenoic acid and docosahexaenoic acid) have anti-inflammatory properties. Omega-3 fatty acids dampen inflammation through multiple pathways. On the one hand, omega-3 fatty acids inhibit the formation of omega-6 fatty acids-derived pro-inflammatory eicosanoids (e.g. PGE2 and LTB4), and on the other hand these fatty acids can form several potent anti-inflammatory lipid mediators (e.g. resolvins and protectins). These together directly or indirectly suppress the activity of nuclear transcription factors, such as NFkappaB, and reduce the production of pro-inflammatory enzymes and cytokines, including COX-2, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-1beta. This chapter focuses on the evidence from recent studies using new experimental models.

Inflammasomes are large, multimeric protein complexes that link the sensing of microbial products and metabolic stress to the proteolytic processing of prointerleukin (pro-IL)-1beta to its active form. NALP1 and NALP2 are founding members of the Nod-like receptor family. Other Nod-like receptors, including NALP3 and NOD2, which are associated with inflammatory disorders, have also been described. The NALP1 and NALP3 inflammasomes are located in the cytoplasm and can, therefore, detect intracellular infection through recognition of microbial pathogen-associated molecular patterns. The inflammasome pathways cooperate with Toll-like receptor pathways to mediate a rapid and appropriate response to pathogens and genotoxic stress. Mutations in both pyrin and NALP3 components of inflammasomes are associated with innate-immune-mediated diseases (familial Mediterranean fever and the 'cryopyrinopathies'), and aberrant IL-1beta processing has been reported in several autoinflammatory conditions, including Muckle-Wells syndrome, chronic infantile neurologic, cutaneous and articular syndrome/neonatal onset multisystem inflammatory disease, and gout. The effectiveness of IL-1beta blockade in treating many of these conditions has transformed the understanding and management of these disorders and also highlighted the role of aberrant IL-1beta signaling in other conditions, such as adult-onset Still's disease and systemic juvenile idiopathic arthritis.

Aging is characterized by changes in the organism's immune functions and stress response, which in the elderly leads to increased incidence of complications and mortality following inflammatory stress. Alterations in the neuro-endocrine axes and overall decline in the immune system play an essential role in this process. Overwhelming evidence however suggests that many cellular cytokine signaling pathways are also affected, thus underscoring the idea that both, "cellular" and "systemic" changes contribute to aging. IL-1beta for example, induces more potent cellular responses in hepatocytes isolated from aged animals then in hepatocytes from young rats. This phenomenon is referred to as IL-1b hyperresponsiveness and is linked to abnormal regulation of various acute phase proteins during aging.Evidence has consistently indicated that activation of neutral sphingomyelinase and the resulting accumulation of ceramide mediate cellular responses to LPS, IL-1beta, and TNFalpha in young animals. More recent studies identified the cytokine-inducible neutral sphingomyelinase with nSMase2 (smpd3) that is localized in the plasma membrane and mediates cellular responses to IL-1beta and TNFalpha. Intriguingly, constitutive up-regulation of nSMase2 occurs in aging and it underlies the hepatic IL-1b hyperresponsiveness. The increased activity of nSMases2 in aging is caused by a substantial decline in hepatic GSH content linking thereby oxidative stress to the onset of pro-inflammatory state in liver. nSMase2 apparently follows a pattern of regulation consisting with "developmental-aging" continuum, since in animal models of delayed aging, like calorie-restricted animals, the aging-associated changes in NSMase activity and function are reversed.

Kinin receptors are involved in the genesis of inflammatory pain. However, there is controversy concerning the mechanism by which B(1) and B(2) kinin receptors mediate inflammatory hypernociception. In the present study, the role of these receptors on inflammatory hypernociception in mice was addressed. Mechanical hypernociception was detected with an electronic pressure meter paw test in mice and cytokines were measured by ELISA. It was observed that in naïve mice a B(2) (d-Arg-Hyp(3), d-Phe(7)-bradykinin) but not a B(1) kinin receptor antagonist (des-Arg(9)-[Leu(8)]-bradykinin, DALBK) inhibited bradykinin- and carrageenin-induced hypernociception. Bradykinin-induced hypernociception was inhibited by indomethacin (5 mg/kg) and guanethidine (30 mg/kg), while not affected by IL-1ra (10 mg/kg) or antibody against keratinocyte-derived chemokine (KC/CXCL-1, 500 ng/paw) or in TNFR1 knockout mice. By contrast, in previously lipopolysaccharide (LPS)-primed mouse paw, B(1) but not B(2) kinin receptor antagonist inhibited bradykinin hypernociception. Furthermore, B(1) kinin receptor agonist induced mechanical hypernociception in LPS-primed mice, which was inhibited by indomethacin, guanethidine, antiserum against TNF-alpha or IL-1ra. This was corroborated by the induction of TNF-alpha and IL-1beta release by B(1) kinin receptor agonist in LPS-primed mouse paws. Moreover, B(1) but not B(2) kinin receptor antagonist inhibited carrageenin-induced hypernociception, and TNF-alpha and IL-1beta release as well, in LPS-primed mice. These results suggest that in naïve mice the B(2) kinin receptor mediates inflammatory hypernociception dependent on prostanoids and sympathetic amines, through a cytokine-independent mechanism. On the other hand, in LPS-primed mice, the B(1) kinin receptor mediates hypernociception by a mechanism dependent on TNF-alpha and IL-1beta, which could stimulate prostanoid and sympathetic amine production.

Oxidative stress and inflammation are fundamental for the onset of aging and appear to be causatively linked. Previously, we reported that hepatocytes from aged rats, compared with young rats, are hyperresponsive to interleukin-1beta (IL-1beta) stimulation and exhibit more potent c-Jun N-terminal kinase (JNK) activation and attenuated interleukin-1 receptor-associated kinase-1 (IRAK-1) degradation. An age-related increase in the activity of neutral sphingomyelinase-2 (NSMase-2), a plasma membrane enzyme, was found to be responsible for the IL-1beta hyperresponsiveness. The results reported here show that increased NSMase activity during aging is caused by a 60-70% decrease in hepatocyte GSH levels. GSH, at concentrations typically found in hepatocytes from young animals, inhibits NSMase activity in a biphasic dose-dependent manner. Inhibition of GSH synthesis in young hepatocytes activates NSMase, causing increased JNK activation and IRAK-1 stabilization in response to IL-1beta, mimicking the hyperresponsiveness typical for aged hepatocytes. Vice versa, increased GSH content in hepatocytes from aged animals by treatment with N-acetylcysteine inhibits NSMase activity and restores normal IL-1beta response. Importantly, the GSH decline, NSMase activation, and IL-1beta hyperresponsiveness are not observed in aged, calorie-restricted rats. In summary, this report demonstrates that depletion of cellular GSH during aging plays an important role in regulating the hepatic response to IL-1beta by inducing NSMase-2 activity.

The proinflammatory cytokine interleukin-1beta (IL-1beta) contributes to inflammation and neuronal death in CNS injuries and neurodegenerative pathologies, and astrocytes have been implicated as the primary mediators of IL-1beta induced neuronal death. As astrocytes play an important role in supporting the survival and functions of neurons, we investigated the effect of plant flavonoids quercetin and luteolin, with known anti-inflammatory properties in modulating the response of human astrocytes to IL-1beta for therapeutic intervention. Flavonoids significantly decreased the release of reactive oxygen species (ROS) from astrocytes stimulated with IL-1beta. This decrease was accompanied by an increase in expression of superoxide dismutase (SOD-1) and thioredoxin (TRX1)-mediators associated with protection against oxidative stress. Flavonoids not only modulated the expression of astrocytes specific molecules such as glial fibrillary acidic protein (GFAP), glutamine synthetase (GS), and ceruloplasmin (CP) both in the presence and absence of IL-1beta but also decreased the elevated levels of proinflammatory cytokine interleukin-6 (IL-6) and chemokines interleukin-8 (IL-8), interferon-inducible protein (IP-10), monocyte-chemoattractant protein-1 (MCP-1), and RANTES from IL-1beta activated astrocytes. Significant decrease in neuronal apoptosis was observed in neurons cultured in conditioned medium obtained from astrocytes treated with a combination of IL-1beta and flavonoids as compared to that treated with IL-1beta alone. Our result suggests that by (i) enhancing the potential of activated astrocytes to detoxify free radical, (ii) reducing the expression of proinflammatory cytokines and chemokines, and (iii) modulating expression of mediators associated with enhanced physiological activity of astrocyte in response to injury, flavonoids confer (iv) protection against IL-1beta induced astrocyte mediated neuronal damage.

Objective: As a late mediator of inflammation, high mobility group box 1 protein (HMGB1) amplifies the inflammatory responses to tissue injury and infection by inducing and extending the production of proinflammaory cytokines. The aim was to investigate whether HMGB1 mediates such effects by affecting the production of anti-inflammatory mediators., Materials and Methods: The murine macrophage RAW 264.7 cells were stimulated with 0.5 microg/ml of LPS and the levels of HMGB1, TNFalpha, IL-1beta, IL-10 and TGF-beta1 in the culture supernatants were measured by ELISA. Also, the mRNA expression for IL-10 and TGF-beta1 was assessed by RT-PCR., Results: LPS induced HMGB1 release at 8 h and reached a peak at 48 h. Significant (p < 0.05) production of TNFalpha, IL-1beta, IL-10, and TGF-beta1 was seen after 8 h. However, while the levels of TNFalpha and IL-beta remained elevated, IL-10 and TGF-beta1 release markedly declined by 24 h after stimulation. When cells were stimulated in the presence of conditioned medium derived from a 24 h LPS-stimulated culture, the production of TNFalpha and IL-1beta was increased while IL-10 and TGF-beta1 release and mRNA transcripts were decreased. A neutralizing anti-HMGB1 antibody added to the conditioned media reveresed these responses., Conclusions: HMGB1 modulates the inflammatory cascade in activated macrophages by inducing proinflammatory, while suppressing anti-inflammatory responses.

Diabetes causes metabolic and physiologic abnormalities in the retina, and these changes suggest a role for inflammation in the development of diabetic retinopathy. These changes include upregulation of iNOS, COX-2, ICAM-1, caspase 1, VEGF, and NF-kappaB, increased production of nitric oxide, prostaglandin E2, IL-1beta, and cytokines, as well as increased permeability and leukostasis. Using selective pharmacologic inhibitors or genetically modified animals, an increasing number of therapeutic approaches have been identified that significantly inhibit development of at least the early stages of diabetic retinopathy, especially occlusion and degeneration of retinal capillaries. A common feature of a number of these therapies is that they inhibit production of inflammatory mediators. The concept that localized inflammatory processes play a role in the development of diabetic retinopathy is relatively new, but evidence that supports the hypothesis is accumulating rapidly. This new hypothesis offers new insight into the pathogenesis of diabetic retinopathy, and offers novel targets to inhibit the ocular disease.