Soluble Fas ligand drives autoantibody-induced arthritis by binding to DR5/TRAIL-R2
Dongjin JeongHye Sung KimHye Young KimMin Jueng KangHyeryeon JungYumi OhDonghyun KimJaemoon KohSung‐Yup ChoYoon Kyung JeonEun Bong LeeSeung‐Hyo LeeEui‐Cheol ShinHo Min KimEugene C. YiDoo Hyun Chung
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Abstract:
To date, no study has demonstrated that soluble Fas ligand (sFasL)-mediated inflammation is regulated via interaction with Fas in vivo. We found that FasL interacts specifically with tumor necrosis factor receptor superfamily (TNFRSF)10B, also known as death receptor (DR)5. Autoantibody-induced arthritis (AIA) was attenuated in FasL ( Fasl gld/gld )- and soluble FasL ( Fasl Δs/Δs )-deficient mice, but not in Fas ( Fas lpr/lpr and Fas –/– )- or membrane FasL ( Fasl Δm/Δm )-deficient mice, suggesting sFasL promotes inflammation by binding to a Fas-independent receptor. Affinity purification mass spectrometry analysis using human (h) fibroblast-like synovial cells (FLSCs) identified DR5 as one of several proteins that could be the elusive Fas-independent FasL receptor. Subsequent cellular and biochemical analyses revealed that DR5 interacted specifically with recombinant FasL–Fc protein, although the strength of this interaction was approximately 60-fold lower than the affinity between TRAIL and DR5. A microarray assay using joint tissues from mice with arthritis implied that the chemokine CX3CL1 may play an important downstream role of the interaction. The interaction enhanced Cx3cl1 transcription and increased sCX3CL1 production in FLSCs, possibly in an NF-κB-dependent manner. Moreover, the sFasL–DR5 interaction-mediated CX3CL1–CX3CR1 axis initiated and amplified inflammation by enhancing inflammatory cell influx and aggravating inflammation via secondary chemokine production. Blockade of FasL or CX3CR1 attenuated AIA. Therefore, the sFasL–DR5 interaction promotes inflammation and is a potential therapeutic target.Keywords:
Fas ligand
CX3CL1
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Boutonneuse fever
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Mice and rats are the most commonly used animals for preclinical stroke studies, but it is unclear whether targets and mechanisms are always the same across different species. Here, we mapped the baseline expression of a chemokine/cytokine subnetwork and compared responses after oxygen–glucose deprivation in primary neurons, astrocytes, and microglia from mouse, rat, and human. Baseline profiles of chemokines (CX3CL1, CXCL12, CCL2, CCL3, and CXCL10) and cytokines (IL-1α, IL-1β, IL-6, IL-10, and TNFα) showed significant differences between human and rodents. The response of chemokines/cytokines to oxygen–glucose deprivation was also significantly different between species. After 4 h oxygen–glucose deprivation and 4 h reoxygenation, human and rat neurons showed similar changes with a downregulation in many chemokines, whereas mouse neurons showed a mixed response with up- and down-regulated genes. For astrocytes, subnetwork response patterns were more similar in rats and mice compared to humans. For microglia, rat cells showed an upregulation in all chemokines/cytokines, mouse cells had many down-regulated genes, and human cells showed a mixed response with up- and down-regulated genes. This study provides proof-of-concept that species differences exist in chemokine/cytokine subnetworks in brain cells that may be relevant to stroke pathophysiology. Further investigation of differential gene pathways across species is warranted.
CX3CL1
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Summary Background The release of various inflammatory mediators into the bronchial lumen is thought to reflect both the type and degree of airway inflammation, eosinophilic Th2, and Th9, or neutrophilic Th1, and Th17, in patients with asthma. Aims We investigated whether cytokines and chemokines differed in sputum from subjects with more severe compared with milder asthma and whether unbiased factor analysis of cytokine and chemokine groupings indicates specific inflammatory pathways. Methods Cell‐free supernatants from induced sputum were obtained from subjects with a broad range of asthma severity (n = 158) and assessed using Milliplex ® Cytokines/Chemokine kits I, II and III , measuring 75 individual proteins. Each cytokine, chemokine or growth factor concentration was examined for differences between asthma severity groups, for association with leucocyte counts, and by factor analysis. Results Severe asthma subjects had 9 increased and 4 decreased proteins compared to mild asthma subjects and fewer differences compared to moderate asthma. Twenty‐six mediators were significantly associated with an increasing single leucocyte type: 16 with neutrophils (3 interleukins [ IL ], 3 CC chemokines, 4 CXC chemokines, 4 growth factors, TNF ‐ α and CX 3 CL 1/Fractalkine); 5 with lymphocytes ( IL ‐7, IL ‐16, IL ‐23, IFN ‐α2 and CCL 4/ MIP 1β); IL ‐15 and CCL 15/ MIP 1 δ with macrophages; IL ‐5 with eosinophils; and IL ‐4 and TNFSF 10/ TRAIL with airway epithelial cells. Factor analysis grouped 43 cytokines, chemokines and growth factors which had no missing data onto the first 10 factors, containing mixes of Th1, Th2, Th9 and Th17 inflammatory and anti‐inflammatory proteins. Conclusions Sputum cytokines, chemokines and growth factors were increased in severe asthma, primarily with increased neutrophils. Factor analysis identified complex inflammatory protein interactions, suggesting airway inflammation in asthma is characterized by overlapping immune pathways. Thus, focus on a single specific inflammatory mediator or pathway may limit understanding the complexity of inflammation underlying airway changes in asthma and selection of appropriate therapy.
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Fractalkine is the only as yet known member of a novel class of chemokines. Besides its novel Cys‐X‐X‐X‐Cys motif, fractalkine exhibits features which have not been described for any other member of the chemokine family, including its unusual size (397 amino acids human, 395 mouse) and the possession of a transmembrane anchor, from which a soluble form may be released by extracellular cleavage. This report demonstrates the abundant mRNA and fractalkine protein expression in neuronal cells. The neuronal expression of fractalkine mRNA is unaffected by experimentally induced inflammation of central nervous tissue.
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Summary: This experiment provides the quantification of multiple cytokines and chemokines using multiplexed-Luminex technology based on beads containing specific antibodies. Serum cytokine levels reflect chronic or acute inflammation, and circulating cytokines and chemokines are altered in obesity. Cytokines Panel II include IL-16 (interleukin-16), IL-17E/IL-25, IL-21, IL-22, IL-28B, EPO (erythropoietin), Exodus-2 (CCL-21), Fractalkine (CX3CL1), MCP-5 (monocyte chemotactic protein-5; CCL-12), MIP-3α (macrophage inflammatory protein 3-alpha; CCL-20), MIP-3β(macrophage inflammatory protein 3-beta; CCL-19), and TARC (thymus and activation- regulated; CCL-17). A service can be requested for all or any combination of listed cytokines/chemokines for customized multiplexed Luminex assay.
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Abstract Background Noradrenaline (NA) is known to limit neuroinflammation. However, the previously described induction by NA of a chemokine involved in the progression of immune/inflammatory processes, such as chemokine (C-C motif) ligand 2 (CCL2)/monocyte chemotactic protein-1 (MCP-1), apparently contradicts NA anti-inflammatory actions. In the current study we analyzed NA regulation of astroglial chemokine (C-X3-C motif) ligand 1 (CX3CL1), also known as fractalkine, another chemokine to which both neuroprotective and neurodegenerative actions have been attributed. In addition, NA effects on other chemokines and pro-inflammatory mediators were also analyzed. Methods Primary astrocyte-enriched cultures were obtained from neonatal Wistar rats. These cells were incubated for different time durations with combinations of NA and lipopolysaccharide (LPS). The expression and synthesis of different proteins was measured by RT-PCR and enzyme-linked immunosorbent assay (ELISA) or enzyme immunoassays. Data were analyzed by one-way analysis of variance (ANOVA), followed by Newman-Keuls multiple comparison tests. Results The data presented here show that in control conditions, NA induces the production of CX3CL1 in rat cultured astrocytes, but in the presence of an inflammatory stimulus, such as LPS, NA has the opposite effect inhibiting CX3CL1 production. This inversion of NA effect was also observed for MCP-1. Based on the observation of this dual action, NA regulation of different chemokines and pro-inflammatory cytokines was also analyzed, observing that in most cases NA exerts an inhibitory effect in the presence of LPS. One characteristic exception was the induction of cyclooxygenase-2 (COX-2), where a summative effect was detected for both LPS and NA. Conclusion These data suggest that NA effects on astrocytes can adapt to the presence of an inflammatory agent reducing the production of certain cytokines, while in basal conditions NA may have the opposite effect and help to maintain moderate levels of these cytokines.
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Chemokines comprise a group of closely related chemotactic cytokines that are primarily involved in movement of cells [1]. Chemokines are small proteins (mostly 8-14 kDa) and can be classified by structure into four groups (C, CC, CXC, CX3C) defined by the number and spacing of cysteines in highly conserved positions in the N-terminal region of the protein.
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Intraglomerular cellular proliferation is one of the major determinants for dividing various glomerulonephritis (GN) into two groups, such as proliferative versus non-proliferative. Cytokines and chemokines are involved in the pathogenetic pathways and would affect the functional and histologic sequelae. We hypothesized that the morphological difference might be based on the differential intrarenal expression of various cytokines and chemokines. We quantified the intrarenal gene expression of various cytokines and chemokines, and correlated it with clinical parameters.Total RNA was extracted from 54 proliferative GN (PGN) core biopsy specimens and 42 non-proliferative GN (NPGN) specimens. Using the internal competitors, RT-PCR was instituted to quantify mRNAs.The magnitude of the gene expressions of IL-2, IFN-gamma, and IFN-gamma/IL-10 ratio were significantly higher in PGN than in NPGN. RANTES and IL-8 had more abundant gene messages in PGN. It was shown that Th1 cytokine was upregulated if GN was mediated by immune complexes regardless of cellular proliferation. But chemokines had the elevated levels of expression in PGN among immune complex-mediated GN. Up-regulation of the IFN-gamma/IL-10 ratio and TNF-alpha was associated with poor renal function at the time of biopsy. Renal tissues from the patients with a non-nephrotic range of proteinuria showed abundant messages for proinflammatory cytokines and chemokines.Th1, proinflammatory cytokines, and chemokines were more abundant in proliferative GN, and correlated with unfavorable clinical parameters. We propose that the clinical manifestations and diverse histologic features of human GN are associated with differential expressions of specific cytokines and chemokines.
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