Inflammatory responses are controlled by signaling mediators that are regulated by various posttranslational modifications. Recently, transcription-independent functions for glucocorticoids (GC) in ...restraining inflammation have emerged, but the underlying mechanisms are unknown. In this study, we report that GC receptor (GR)-mediated actions of GC acutely suppress TLR9-induced inflammation via inhibition of IL-1R-associated kinase 1 (IRAK1) ubiquitination. β-TrCP-IRAK1 interaction is required for K48-linked ubiquitination of IRAK1 at Lys
and subsequent membrane-to-cytoplasm trafficking of IRAK1 interacting partners TNFR-associated factor 6 and TAK1 that facilitates NF-κB and MAPK activation. Upon costimulation of macrophages with GC and TLR9-engaging ligand, GR physically interacts with IRAK1 and interferes with protein-protein interactions between β-TrCP and IRAK1. Ablation of GR in macrophages prevents GC-dependent suppression of β-TrCP-IRAK1 interactions. This GC-mediated suppression of IRAK1 activation is unique to TLR9, as GC treatment impairs TLR9 but not TLR4 ligand-induced K48-linked IRAK1 ubiquitination and trafficking of IRAK1 interacting partners. Furthermore, mutations in IRAK1 at Lys
prevent TLR9 ligand-induced activation of inflammatory signaling mediators and synthesis of proinflammatory cytokines to an extent comparable to GC-mediated inhibition. Collectively, these findings identify a transcription-independent, rapid, and nongenomic GC suppression of TLR9 ligand-mediated IRAK1 ubiquitination as a novel mechanism for restraining acute inflammatory reactions.
To explore the role of glucocorticoids in regulation of kinase pathways during innate immune responses, we generated mice with conditional deletion of glucocorticoid receptor (GR) in macrophages ...(MGRKO). Activation of toll-like receptor 4 (TLR4) by lipopolysaccharide (LPS) caused greater mortality and cytokine production in MGRKO mice than in controls. Ex vivo, treatment with dexamethasone (Dex) markedly inhibited LPS-mediated induction of inflammatory genes in control but not GR-deficient macrophages. We show that Dex inhibits p38 MAPK, but not PI3K/Akt, ERK, or JNK, in control macrophages. Associated with p38 inhibition, Dex induced MAP kinase phosphatase-1 (MKP-1) in control, but not MGRKO, macrophages. Consistent with the ex vivo studies, treatment with a p38 MAPK–specific inhibitor resulted in rescue of MGRKO mice from LPS-induced lethality. Taken together, we identify p38 MAPK and its downstream targets as essential for GR-mediated immunosuppression in macrophages.
Endogenous and pharmacologic glucocorticoids (GCs) limit inflammatory cascades initiated by Toll-like receptor (TLR) activation. A long-standing clinical observation has been the delay between GC ...administration and the manifestation of GC's anti-inflammatory actions. We hypothesized that the GCs would have inhibitory effects that target late temporal pathways that propagate proinflammatory signals. Here we interrogated signal transducer and activator of transcription 1 (STAT1) regulation by GC and its consequences for cytokine production during activation of macrophages with TLR-specific ligands. We found that robust STAT1 activation does not occur until 2–3 h after TLR engagement, and that GC suppression of STAT1 phosphorylation first manifests at this time. GC attenuates TLR4-mediated STAT1 activation only through induction of suppressor of cytokine signaling 1 (SOCS1), which increases throughout the 6-h period after treatment. Inhibition of TLR3-mediated STAT1 activation occurs via two mechanisms, impairment of type I IFN secretion and induction of SOCS1. Our data show that SOCS1 and type I interferons are critical GC targets for regulating STAT1 activity and may account for overall GC effectiveness in inflammation suppression in the clinically relevant time frame.
There have been accounts of repeated failure of crane hooks at the coil yard of a Hot Strip Mill which pose a serious threat to safety in the area. More than 4 hooks failed in less than 5 years. The ...crane hook (rated for 36000 kg) failed from the threaded shank while lifting a load of 18143 kg. The metal in the hook was revealed by chemical analysis to be killed IS: 4367 20C15 steel. The hook rod failed from a step where there was a cross sectional change and the locations were associated with machining and chatter marks. Such cross-sectional changes are the potential sites of stress concentrations leading to crack initiations. Fracture surfaces of broken pieces of hook reveal initiation of beach marks from both sides with granular rough surface at the middle of fracture zone. Beach marks initiated from both sides indicate origin of reverse bending fatigue. Distinct granular rough zone at the middle is due to final brittle fracture. Microstructure of the polished sample revealed numerous inclusions which indicate that the steel was not clean .Such a huge number of inclusions are not desirable as they can act as stress concentration sites and lead to fatigue crack initiation. Etched microstructure of failed hook reveals coarse cast structure having inhomogeneous microstructure with a mixture of ferrite and pearlite (which meant lower fatigue strength). This inhomogeneous coarser cast structure is outcome of lower reduction ratio during rolling followed by improper heat treatment process. The fracture was concluded to have occurred due to stress concentration from the step region due to inferior material (Inclusion and Improper Heat treatment process). Preventive maintenance and condition monitoring procedures should be applied to identify and minimize the risk(s) Establishment of an NDT procedure for regular basis inspection of the structural members (welded joints and hookshaped steel rods during incoming inspection and in-service).
•The CR sheets have been analyzed with the sliver defects.•In sample #1 the slag entrapment of the mold fluxes is the main origin of the defects.•In sample #2 alumina formed is deposited in tundish ...nozzle entrapped during solidification.•These entrapped translate into long streaks of defects called slivers during CR.
An authoritative guide to an in-depth analysis of various state-of-the-art data clustering approaches using a range of computational intelligence techniques Recent Advances in Hybrid Metaheuristics ...for Data Clustering offers a guide to the fundamentals of various metaheuristics and their application to data clustering. Metaheuristics are designed to tackle complex clustering problems where classical clustering algorithms have failed to be either effective or efficient. The authors-noted experts on the topic-provide a text that can aid in the design and development of hybrid metaheuristics to be applied to data clustering. The book includes performance analysis of the hybrid metaheuristics in relationship to their conventional counterparts. In addition to providing a review of data clustering, the authors include in-depth analysis of different optimization algorithms. The text offers a step-by-step guide in the build-up of hybrid metaheuristics and to enhance comprehension. In addition, the book contains a range of real-life case studies and their applications. This important text: Includes performance analysis of the hybrid metaheuristics as related to their conventional counterparts Offers an in-depth analysis of a range of optimization algorithms Highlights a review of data clustering Contains a detailed overview of different standard metaheuristics in current use Presents a step-by-step guide to the build-up of hybrid metaheuristics Offers real-life case studies and applications Written for researchers, students and academics in computer science, mathematics, and engineering, Recent Advances in Hybrid Metaheuristics for Data Clustering provides a text that explores the current data clustering approaches using a range of computational intelligence techniques.
Human and rodent studies indicate a role for circadian rhythmicity and associated clock gene expression in supporting normal parturition. The importance of clock gene expression in tissues besides ...the suprachiasmatic nucleus is emerging. Here, a Bmal1 conditional knockout mouse line and a novel Cre transgenic mouse line were used to examine the role of myometrial Bmal1 in parturition. Ninety-two percent (22/24) of control females but only 64% (14/22) of females with disrupted myometrial Bmal1 completed parturition during the expected time window of 5p.m. on Day 19 through to 9a.m. on Day 19.5 of gestation. However, neither serum progesterone levels nor uterine transcript expression of the contractile-associated proteins Connexin43 and Oxytocin receptor differed between females with disrupted myometrial Bmal1 and controls during late gestation. The data indicate a role for myometrial Bmal1 in maintaining normal time of day of parturition.
Glucocorticoids and the Osteoclast KIM, HYUN-JU; ZHAO, HAIBO; KITAURA, HIDEKI ...
Annals of the New York Academy of Sciences,
November 2007, Letnik:
1116, Številka:
1
Journal Article
Recenzirano
: Glucocorticoid (GC)‐induced bone loss is the most common cause of secondary osteoporosis but its pathogenesis is controversial. GCs clearly suppress bone formation in vivo but the means by which ...they impact osteoblasts is unclear. Because bone remodeling is characterized by tethering of the activities of the two cells, the osteoclast is a potential modulator of the effect of GCs on osteoblasts. To address this issue we compared the effects of dexamethasone on wild‐type (WT) osteoclasts with those derived from mice with disruption of the GC receptor in osteoclast lineage cells and found that the bone‐degrading capacity of GC‐treated WT cells is suppressed. The inhibitory effect of dexamethasone on bone resorption reflects failure of osteoclasts to organize their cytoskeleton in response to M‐CSF. Dexamethasone specifically arrests M‐CSF activation of RhoA, Rac, and Vav3, each of which regulate the osteoclast cytoskeleton. In all circumstances, mice lacking the GC receptor in osteoclast lineage cells are spared the impact of dexamethasone on osteoclasts and their precursors. Consistent with osteoclasts modulating the osteoblast‐suppressive effect of dexamethasone, GC receptor‐deficient mice are protected from the steroid's inhibition of bone formation.
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