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Role of HNF4alpha in the superinduction of the IL-1beta-activated iNOS gene by oxidative stress.

ABSTRACT: IL-1beta (interleukin-1beta) treatment of hepatocytes results in an NF-kappaB (nuclear factor-kappaB)-mediated activation of the iNOS (induced nitric oxide synthase) gene, and this increase in gene expression is further augmented by oxidative stress. Oxidative stress alone has no influence on the iNOS promoter, therefore indicating that the promoter needs to be primed by NF-kappaB. In this issue of the Biochemical Journal, Guo et al. extend their earlier work, showing that HNF4alpha (hepatocyte nuclear factor 4alpha) mediates the superinduction of iNOS observed by co-treating cells with IL-1b plus H2O2. A specific phosphorylation by p38 kinase at Ser-158 of HNF4alpha results in increased binding of HNF4alpha to the iNOS promoter, leading to enhanced transcription. The study by Guo et al. is the first to show definitively that HNF4alpha can be modulated to differentially activate specific genes. However, issues remain to determine the functional significance in vivo of the elevated iNOS activity, and the mechanism that governs the specificity of HNF4alpha towards the iNOS promoter element as compared with many other HNF4alpha target genes in the hepatocyte.

SUBMITTER: Gonzalez FJ

PROVIDER: S-EPMC1408685 | biostudies-other | 2006 Mar

REPOSITORIES: biostudies-other

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Cannabidiol in vivo blunts beta-amyloid induced neuroinflammation by suppressing IL-1beta and iNOS expression.

Project description:BACKGROUND AND PURPOSE: Pharmacological inhibition of beta-amyloid (Abeta) induced reactive gliosis may represent a novel rationale to develop drugs able to blunt neuronal damage and slow the course of Alzheimer's disease (AD). Cannabidiol (CBD), the main non-psychotropic natural cannabinoid, exerts in vitro a combination of neuroprotective effects in different models of Abeta neurotoxicity. The present study, performed in a mouse model of AD-related neuroinflammation, was aimed at confirming in vivo the previously reported antiinflammatory properties of CBD. EXPERIMENTAL APPROACH: Mice were inoculated with human Abeta (1-42) peptide into the right dorsal hippocampus, and treated daily with vehicle or CBD (2.5 or 10 mg kg(-1), i.p.) for 7 days. mRNA for glial fibrillary acidic protein (GFAP) was assessed by in situ hybridization. Protein expression of GFAP, inducible nitric oxide synthase (iNOS) and IL-1beta was determined by immunofluorescence analysis. In addition, ELISA assay of IL-1beta level and the measurement of NO were performed in dissected and homogenized ipsilateral hippocampi, derived from vehicle and Abeta inoculated mice, in the absence or presence of CBD. KEY RESULTS: In contrast to vehicle, CBD dose-dependently and significantly inhibited GFAP mRNA and protein expression in Abeta injected animals. Moreover, under the same experimental conditions, CBD impaired iNOS and IL-1beta protein expression, and the related NO and IL-1beta release. CONCLUSION AND IMPLICATIONS: The results of the present study confirm in vivo anti-inflammatory actions of CBD, emphasizing the importance of this compound as a novel promising pharmacological tool capable of attenuating Abeta evoked neuroinflammatory responses.

| S-EPMC2189818 | biostudies-other

Cytokine signaling-1 suppressor is inducible by IL-1beta and inhibits the catabolic effects of IL-1beta in chondrocytes: its implication in the paradoxical joint-protective role of IL-1beta.

Project description:Although IL-1? is believed to be crucial in the pathogenesis of osteoarthritis (OA), the IL-1? blockade brings no therapeutic benefit in human OA and results in OA aggravation in several animal models. We explored the role of a cytokine signaling 1 (SOCS1) suppressor as a regulatory modulator of IL-1? signaling in chondrocytes.Cartilage samples were obtained from patients with knee OA and those without OA who underwent surgery for femur-neck fracture. SOCS1 expression in cartilage was assessed with immunohistochemistry. IL-1?-induced SOCS1 expression in chondrocytes was analyzed with quantitative polymerase chain reaction and immunoblot. The effect of SOCS1 on IL-1? signaling pathways and the synthesis of matrix metalloproteinases (MMPs) and aggrecanase-1 was investigated in SOCS1-overexpressing or -knockdown chondrocytes.SOCS1 expression was significantly increased in OA cartilage, especially in areas of severe damage (P?<?0.01). IL-1? stimulated SOCS1 mRNA expression in a dose-dependent pattern (P?<?0.01). The IL-1?-induced production of MMP-1, MMP-3, MMP-13, and ADAMTS-4 (aggrecanase-1, a disintegrin and metalloproteinase with thrombospondin motifs 4) was affected by SOCS1 overexpression or knockdown in both SW1353 cells and primary human articular chondrocytes (all P values?<?0.05). The inhibitory effects of SOCS1 were mediated by blocking p38, c-Jun N-terminal kinase (JNK), and nuclear factor ?B (NF-?B) activation, and by downregulating transforming growth factor-?-activated kinase 1 (TAK1) expression.Our results show that SOCS1 is induced by IL1-? in OA chondrocytes and suppresses the IL-1?-induced synthesis of matrix-degrading enzymes by inhibiting IL-1? signaling at multiple levels. It suggests that the IL-1?-inducible SOCS1 acts as a negative regulator of the IL-1? response in OA cartilage.

| S-EPMC3979110 | biostudies-literature

PMN transendothelial migration decreases nuclear NFkappaB in IL-1beta-activated endothelial cells: role of PECAM-1.

Project description:During the systemic inflammatory response, circulating cytokines interact with the vascular endothelium, resulting in activation and nuclear accumulation of the nuclear transcription factor, nuclear factor kappa B (NFkappaB). In turn, NFkappaB transactivates relevant proinflammatory genes, resulting in an amplification of the inflammatory response. Because this scenario is potentially detrimental to the host, mechanisms exist to limit this amplification. Using an in vitro system that mimics the vascular-interstitial interface during inflammation (cell culture inserts), we provide evidence for the existence of a novel negative feedback mechanism on NFkappaB activity. We show that the interleukin 1beta-induced accumulation of nuclear NFkappaB in human umbilical vein endothelial cell monolayers is dramatically reduced when polymorphonuclear leukocytes (PMN) are allowed to migrate across these monolayers. This effect does not appear to be due to PMN-derived elastase or nitric oxide. Fixed PMN (adhere but do not migrate) did not affect nuclear NFkappaB. Furthermore, cross-linking of platelet-endothelial cell adhesion molecule-1 (PECAM-1), but not intercellular adhesion molecule-1, reduces human umbilical vein endothelial cell nuclear NFkappaB induced by interleukin 1beta. Finally, interaction of PMN with PECAM-1-deficient endothelial cells does not reduce nuclear NFkappaB. These observations indicate that engagement of PECAM-1 by emigrating PMN is a pivotal event in this negative feedback on NFkappaB activity.

| S-EPMC2172941 | biostudies-other

Autophagy controls IL-1beta secretion by targeting pro-IL-1beta for degradation.

Project description:Autophagy is a key regulator of cellular homeostasis that can be activated by pathogen-associated molecules and recently has been shown to influence IL-1β secretion by macrophages. However, the mechanisms behind this are unclear. Here, we describe a novel role for autophagy in regulating the production of IL-1β in antigen-presenting cells. After treatment of macrophages with Toll-like receptor ligands, pro-IL-1β was specifically sequestered into autophagosomes, whereas further activation of autophagy with rapamycin induced the degradation of pro-IL-1β and blocked secretion of the mature cytokine. Inhibition of autophagy promoted the processing and secretion of IL-1β by antigen-presenting cells in an NLRP3- and TRIF-dependent manner. This effect was reduced by inhibition of reactive oxygen species but was independent of NOX2. Induction of autophagy in mice in vivo with rapamycin reduced serum levels of IL-1β in response to challenge with LPS. These data demonstrate that autophagy controls the production of IL-1β through at least two separate mechanisms: by targeting pro-IL-1β for lysosomal degradation and by regulating activation of the NLRP3 inflammasome.

| S-EPMC3058966 | biostudies-literature

Cross-talk between interleukin 1beta (IL-1beta) and IL-6 signalling pathways: IL-1beta selectively inhibits IL-6-activated signal transducer and activator of transcription factor 1 (STAT1) by a proteasome-dependent mechanism.

Project description:Interleukin 1beta (IL-1beta) suppresses the IL-6-dependent induction of type II acute-phase response genes, but the underlying mechanism for this suppression remains uncertain. Here we report that treatment of human hepatocullular carcinoma HepG2 cells with IL-1beta inhibited the IL-6-dependent binding of signal transducer and activator of transcription factor (STAT)1, but not that of STAT3, to the high-affinity serum-inducible element ('SIE'). Furthermore, IL-1beta selectively down-regulated the IL-6-induced tyrosine phosphorylation of STAT1 without affecting the level of STAT1 or tyrosine phosphorylation of STAT3. Kinase assays in vitro indicated that the inhibition of STAT1 phosphorylation by IL-1beta was not due to an upstream blockade of Janus kinase (JAK1 or JAK2) activation. However, pretreatment with the proteasome inhibitor MG132 under conditions that prevented the IL-1beta-dependent activation of the nuclear factor NF-kappaB also blocked the inhibitory effect of IL-1beta on IL-6-activated STAT1. In related experiments, the protein tyrosine phosphatase inhibitor Na(3)VO(4) also antagonized the inhibitory effect of IL-1beta on the activation of STAT1 by IL-6. Taken together, these findings indicate that, by using a proteasome-dependent mechanism, IL-1beta concomitantly induces NF-kappaB activation and dephosphorylates IL-6-activated STAT1; the latter might partly account for the inhibition by IL-1beta of the IL-6-dependent induction of type II acute-phase genes.

| S-EPMC1221534 | biostudies-other

Synovial fibroblast activated by IL-1beta; effect of prostacyclin signaling

Project description:Synovial fibroblasts were extracted from knee joints of naïve mice(DBA/1J, male 8-12 week old), and passaged 3-4 times. Cells were plated at a concentration of 1 X 106 cells/dish in 60 mm dish in 5 ml of RPMI1640 medium with 1% heat-inactivated FCS at 37°C, 5% CO2. Cells were treated vehicle or stimulated by IL-1beta. In IL-1beta(5ng/ml) stimulated groups, indomethacin (1 μM) and iloprost (1μM) were further added either alone or in combination. After 6 hour stimulation as described above, cells were isolated and frozen by liquid nitrogen, and stored at –80°C before use. Total RNA was extracted by RNAeasy Mini Kit. The RNA sample was labeled for hybridization onto the genechip array according to the standard affymetrix protcols. Keywords = arthritis prostacyclin Keywords: other

2005-05-20 | GSE2676 | GEO

Vagotomy blocks the induction of interleukin-1beta (IL-1beta) mRNA in the brain of rats in response to systemic IL-1beta.

Project description:There is considerable interest in the mechanisms by which systemic cytokines signal the CNS to elicit centrally controlled biological actions. This study determined the effects of intraperitoneal injections of interleukin-1beta (IL-1beta) on IL-1beta mRNA and IL-1 receptor accessory protein (IL-1RAP) mRNA production in rat liver and brain using the reverse transcription-PCR. Saline or IL-1beta (0.5 microg/kg) was injected intraperitoneally in subdiaphragmatically vagotomized and sham-operated (SHAM) rats. All injections were performed at dark onset, and rats were killed 2 hr after the injection. In SHAM rats, IL-1beta increased IL-1beta mRNA levels in the liver, hypothalamus, hippocampus, and brainstem. Subdiaphragmatic vagotomy blocked the IL-1beta-induced increase in IL-1beta mRNA in the brainstem and hippocampus and significantly attenuated the increase in the hypothalamus. Vagotomy did not affect IL-1beta-induced IL-1beta mRNA production in the liver. IL-1RAP mRNA was highly expressed in each region examined; however, no significant differences in IL-1RAP mRNA production were found in any region after IL-1beta injection. The current results indicate that the vagus nerve is involved in transmitting cytokine signals to the brain and suggest that the induction of brain cytokines is a critical step in the pathway by which vagal-mediated signals result in centrally controlled symptoms of the acute phase response.

| S-EPMC6792909 | biostudies-literature

The CDK domain of p21 is a suppressor of IL-1beta-mediated inflammation in activated macrophages.

Project description:Significant morbidity and mortality can be attributed to inflammatory diseases; therefore, a greater understanding of the mechanisms involved in the progression of inflammation is crucial. Here, we demonstrate that p21((WAF1/CIP1)), an established suppressor of cell cycle progression, is a inhibitor of IL-1beta synthesis in macrophages. Mice deficient in p21 (p21(-/-)) display increased susceptibility to endotoxic shock, which is associated with increased serum levels of IL-1beta. Administration of IL-1 receptor antagonist reduces LPS-induced lethality in p21(-/-) mice. Analysis of isolated macrophages, which are one of the central producers of IL-1beta, reveals that deficiency for p21 led to more IL-1beta mRNA and pro-protein synthesis following TLR ligation. The increase in IL-1beta pro-protein is associated with elevated secretion of active IL-1beta by p21(-/-) macrophages. siRNA-mediated knockdown of p21 in human macrophages results in increased IL-1beta secretion as well. A peptide mapping strategy shows that the cyclin-dependent-kinase (CDK)-binding domain of p21 is sufficient to reduce the secretion of IL-1beta by p21(-/-) macrophages. These data suggest a novel role for p21 and specifically for the CDK-binding domain of p21((WAF1/CIP1)) in inhibiting inflammation.

| S-EPMC2734089 | biostudies-literature

IL-1beta is an essential mediator of the antineurogenic and anhedonic effects of stress.

Project description:Stress decreases neurogenesis in the adult hippocampus, and blockade of this effect is required for the actions of antidepressants in behavioral models of depression. However, the mechanisms underlying these effects of stress have not been identified. Here, we demonstrate an essential role for the proinflammatory cytokine IL-1beta. Administration of IL-1beta or acute stress suppressed hippocampal cell proliferation. Blockade of the IL-1beta receptor, IL-1RI, by using either an inhibitor or IL-1RI null mice blocks the antineurogenic effect of stress and blocks the anhedonic behavior caused by chronic stress exposure. In vivo and in vitro studies demonstrate that hippocampal neural progenitor cells express IL-1RI and that activation of this receptor decreases cell proliferation via the nuclear factor-kappaB signaling pathway. These findings demonstrate that IL-1beta is a critical mediator of the antineurogenic and depressive-like behavior caused by acute and chronic stress.

| S-EPMC2206608 | biostudies-literature

Comparison of gene expression in the intestinal metaplasia in Cdx2/IL-1beta mice vs IL-1beta alone

Project description:Cdx2/IL-1beta mice have less intestinal metaplasia at the squamocolumnar junction thanIL-1beta mice alone. This study was to identify a mechanism for this effect by examining differences in gene expression patterns when Cdx2 is co-expressed.

2016-08-01 | GSE60320 | GEO

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