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cytokines, both proinflammatory and anti-inflammatory, have been detected in the ST of RA, and the balance between these opposing cytokine activities regulates disease severity [10]. Endogenous IL-10, produced mainly by macrophages and T cells, inhibits proinflammatory cytokine production by ST cells [12]. However, this regulatory activity seems to be restricted during chronic inflammation. The activation of both the extracellular stimulus-regulated kinase and p38 kinase pathways, induced by TNF-α and IL-1, inhibits the Jak1–STAT3 signaling pathway shared by IL-10 and IL-6 in adhered macrophages [13]. More importantly, IL-10-mediated STAT3 activation is mostly undetectable in RA synovial macrophages. This impaired IL-10 signaling is probably induced by chronic exposure to immune complexes in vivo, because both cell surface IL-10R1 expression and IL-10-induced Jak1 activation are suppressed in IFN-γ-primed macrophages by a protein kinase C-dependent pathway following ligation of the IgG Fc gamma receptor [14]. Furthermore, dendritic cells from RA synovial fluids are resistant to the immunoregulatory effect of IL-10 due to decreased transport of intracellular IL-10R1 in the presence of proinflammatory cytokine stimuli such as TNF-α, IL-1, and granulocyte–macrophage colony-stimulating factor [15]. We have demonstrated that the resistance of RA CD4+ T cells to IL-10 may be associated with defective IL-10-dependent STAT3 activation, but not with IL-10R1 expression. Inhibitory effects of IL-10 on these inflammatory cell types are therefore differentially modulated at the signal transduction level under the inflammatory environment in RA."}

{"project":"bionlp-st-ge-2016-coref","denotations":[{"id":"T23319","span":{"begin":1270,"end":1318},"obj":"Antecedent"},{"id":"T23318","span":{"begin":1260,"end":1264},"obj":"Antecedent"},{"id":"T23317","span":{"begin":1253,"end":1258},"obj":"Antecedent"},{"id":"T23316","span":{"begin":1212,"end":1244},"obj":"Anaphor"}],"relations":[{"id":"R11365","pred":"boundBy","subj":"T23316","obj":"T23317"},{"id":"R11366","pred":"boundBy","subj":"T23316","obj":"T23318"},{"id":"R11367","pred":"boundBy","subj":"T23316","obj":"T23319"}],"namespaces":[{"prefix":"_base","uri":"https://bionlp.dbcls.jp/ontology/ge.owl#"}],"text":"Numerous cytokines, both proinflammatory and anti-inflammatory, have been detected in the ST of RA, and the balance between these opposing cytokine activities regulates disease severity [10]. Endogenous IL-10, produced mainly by macrophages and T cells, inhibits proinflammatory cytokine production by ST cells [12]. However, this regulatory activity seems to be restricted during chronic inflammation. The activation of both the extracellular stimulus-regulated kinase and p38 kinase pathways, induced by TNF-α and IL-1, inhibits the Jak1–STAT3 signaling pathway shared by IL-10 and IL-6 in adhered macrophages [13]. More importantly, IL-10-mediated STAT3 activation is mostly undetectable in RA synovial macrophages. This impaired IL-10 signaling is probably induced by chronic exposure to immune complexes in vivo, because both cell surface IL-10R1 expression and IL-10-induced Jak1 activation are suppressed in IFN-γ-primed macrophages by a protein kinase C-dependent pathway following ligation of the IgG Fc gamma receptor [14]. Furthermore, dendritic cells from RA synovial fluids are resistant to the immunoregulatory effect of IL-10 due to decreased transport of intracellular IL-10R1 in the presence of proinflammatory cytokine stimuli such as TNF-α, IL-1, and granulocyte–macrophage colony-stimulating factor [15]. We have demonstrated that the resistance of RA CD4+ T cells to IL-10 may be associated with defective IL-10-dependent STAT3 activation, but not with IL-10R1 expression. Inhibitory effects of IL-10 on these inflammatory cell types are therefore differentially modulated at the signal transduction level under the inflammatory environment in RA."}

{"project":"bionlp-st-ge-2016-test-proteins","denotations":[{"id":"T23416","span":{"begin":1516,"end":1521},"obj":"Protein"},{"id":"T23415","span":{"begin":1474,"end":1481},"obj":"Protein"},{"id":"T23414","span":{"begin":1443,"end":1448},"obj":"Protein"},{"id":"T23413","span":{"begin":1427,"end":1432},"obj":"Protein"},{"id":"T23412","span":{"begin":1388,"end":1393},"obj":"Protein"},{"id":"T23411","span":{"begin":1372,"end":1375},"obj":"Protein"},{"id":"T23410","span":{"begin":1270,"end":1318},"obj":"Protein"},{"id":"T23409","span":{"begin":1260,"end":1264},"obj":"Protein"},{"id":"T23408","span":{"begin":1253,"end":1258},"obj":"Protein"},{"id":"T23407","span":{"begin":1185,"end":1192},"obj":"Protein"},{"id":"T23406","span":{"begin":1135,"end":1140},"obj":"Protein"},{"id":"T23405","span":{"begin":915,"end":920},"obj":"Protein"},{"id":"T23404","span":{"begin":881,"end":885},"obj":"Protein"},{"id":"T23403","span":{"begin":867,"end":872},"obj":"Protein"},{"id":"T23402","span":{"begin":844,"end":851},"obj":"Protein"},{"id":"T23401","span":{"begin":733,"end":738},"obj":"Protein"},{"id":"T23400","span":{"begin":651,"end":656},"obj":"Protein"},{"id":"T23399","span":{"begin":636,"end":641},"obj":"Protein"},{"id":"T23398","span":{"begin":584,"end":588},"obj":"Protein"},{"id":"T23397","span":{"begin":574,"end":579},"obj":"Protein"},{"id":"T23396","span":{"begin":540,"end":545},"obj":"Protein"},{"id":"T23395","span":{"begin":535,"end":539},"obj":"Protein"},{"id":"T23394","span":{"begin":516,"end":520},"obj":"Protein"},{"id":"T23393","span":{"begin":506,"end":511},"obj":"Protein"},{"id":"T23392","span":{"begin":203,"end":208},"obj":"Protein"}],"namespaces":[{"prefix":"_base","uri":"http://bionlp.dbcls.jp/ontology/ge.owl#"}],"text":"Numerous cytokines, both proinflammatory and anti-inflammatory, have been detected in the ST of RA, and the balance between these opposing cytokine activities regulates disease severity [10]. Endogenous IL-10, produced mainly by macrophages and T cells, inhibits proinflammatory cytokine production by ST cells [12]. However, this regulatory activity seems to be restricted during chronic inflammation. The activation of both the extracellular stimulus-regulated kinase and p38 kinase pathways, induced by TNF-α and IL-1, inhibits the Jak1–STAT3 signaling pathway shared by IL-10 and IL-6 in adhered macrophages [13]. More importantly, IL-10-mediated STAT3 activation is mostly undetectable in RA synovial macrophages. This impaired IL-10 signaling is probably induced by chronic exposure to immune complexes in vivo, because both cell surface IL-10R1 expression and IL-10-induced Jak1 activation are suppressed in IFN-γ-primed macrophages by a protein kinase C-dependent pathway following ligation of the IgG Fc gamma receptor [14]. Furthermore, dendritic cells from RA synovial fluids are resistant to the immunoregulatory effect of IL-10 due to decreased transport of intracellular IL-10R1 in the presence of proinflammatory cytokine stimuli such as TNF-α, IL-1, and granulocyte–macrophage colony-stimulating factor [15]. We have demonstrated that the resistance of RA CD4+ T cells to IL-10 may be associated with defective IL-10-dependent STAT3 activation, but not with IL-10R1 expression. Inhibitory effects of IL-10 on these inflammatory cell types are therefore differentially modulated at the signal transduction level under the inflammatory environment in RA."}

{"project":"bionlp-st-ge-2016-uniprot","denotations":[{"id":"T26420","span":{"begin":584,"end":588},"obj":"http://www.uniprot.org/uniprot/P05231"},{"id":"T26398","span":{"begin":1443,"end":1448},"obj":"http://www.uniprot.org/uniprot/P40763"},{"id":"T26397","span":{"begin":651,"end":656},"obj":"http://www.uniprot.org/uniprot/P40763"},{"id":"T26396","span":{"begin":540,"end":545},"obj":"http://www.uniprot.org/uniprot/P40763"},{"id":"T26379","span":{"begin":915,"end":920},"obj":"http://www.uniprot.org/uniprot/P01579"},{"id":"T26353","span":{"begin":1516,"end":1521},"obj":"http://www.uniprot.org/uniprot/P22301"},{"id":"T26352","span":{"begin":1427,"end":1432},"obj":"http://www.uniprot.org/uniprot/P22301"},{"id":"T26351","span":{"begin":1388,"end":1393},"obj":"http://www.uniprot.org/uniprot/P22301"},{"id":"T26350","span":{"begin":1135,"end":1140},"obj":"http://www.uniprot.org/uniprot/P22301"},{"id":"T26349","span":{"begin":867,"end":872},"obj":"http://www.uniprot.org/uniprot/P22301"},{"id":"T26348","span":{"begin":733,"end":738},"obj":"http://www.uniprot.org/uniprot/P22301"},{"id":"T26347","span":{"begin":636,"end":641},"obj":"http://www.uniprot.org/uniprot/P22301"},{"id":"T26346","span":{"begin":574,"end":579},"obj":"http://www.uniprot.org/uniprot/P22301"},{"id":"T26345","span":{"begin":203,"end":208},"obj":"http://www.uniprot.org/uniprot/P22301"},{"id":"T26458","span":{"begin":1253,"end":1258},"obj":"http://www.uniprot.org/uniprot/P01375"},{"id":"T26457","span":{"begin":506,"end":511},"obj":"http://www.uniprot.org/uniprot/P01375"},{"id":"T26456","span":{"begin":1253,"end":1256},"obj":"http://www.uniprot.org/uniprot/P01375"},{"id":"T26455","span":{"begin":506,"end":509},"obj":"http://www.uniprot.org/uniprot/P01375"},{"id":"T24245","span":{"begin":1372,"end":1375},"obj":"http://www.uniprot.org/uniprot/P01730"}],"namespaces":[{"prefix":"_base","uri":"http://www.uniprot.org/uniprot/"}],"text":"Numerous cytokines, both proinflammatory and anti-inflammatory, have been detected in the ST of RA, and the balance between these opposing cytokine activities regulates disease severity [10]. Endogenous IL-10, produced mainly by macrophages and T cells, inhibits proinflammatory cytokine production by ST cells [12]. However, this regulatory activity seems to be restricted during chronic inflammation. The activation of both the extracellular stimulus-regulated kinase and p38 kinase pathways, induced by TNF-α and IL-1, inhibits the Jak1–STAT3 signaling pathway shared by IL-10 and IL-6 in adhered macrophages [13]. More importantly, IL-10-mediated STAT3 activation is mostly undetectable in RA synovial macrophages. This impaired IL-10 signaling is probably induced by chronic exposure to immune complexes in vivo, because both cell surface IL-10R1 expression and IL-10-induced Jak1 activation are suppressed in IFN-γ-primed macrophages by a protein kinase C-dependent pathway following ligation of the IgG Fc gamma receptor [14]. Furthermore, dendritic cells from RA synovial fluids are resistant to the immunoregulatory effect of IL-10 due to decreased transport of intracellular IL-10R1 in the presence of proinflammatory cytokine stimuli such as TNF-α, IL-1, and granulocyte–macrophage colony-stimulating factor [15]. We have demonstrated that the resistance of RA CD4+ T cells to IL-10 may be associated with defective IL-10-dependent STAT3 activation, but not with IL-10R1 expression. Inhibitory effects of IL-10 on these inflammatory cell types are therefore differentially modulated at the signal transduction level under the inflammatory environment in RA."}

{"project":"UBERON-AE","denotations":[{"id":"T22788","span":{"begin":1071,"end":1086},"obj":"http://purl.obolibrary.org/obo/UBERON_0001090"}],"text":"Numerous cytokines, both proinflammatory and anti-inflammatory, have been detected in the ST of RA, and the balance between these opposing cytokine activities regulates disease severity [10]. Endogenous IL-10, produced mainly by macrophages and T cells, inhibits proinflammatory cytokine production by ST cells [12]. However, this regulatory activity seems to be restricted during chronic inflammation. The activation of both the extracellular stimulus-regulated kinase and p38 kinase pathways, induced by TNF-α and IL-1, inhibits the Jak1–STAT3 signaling pathway shared by IL-10 and IL-6 in adhered macrophages [13]. More importantly, IL-10-mediated STAT3 activation is mostly undetectable in RA synovial macrophages. This impaired IL-10 signaling is probably induced by chronic exposure to immune complexes in vivo, because both cell surface IL-10R1 expression and IL-10-induced Jak1 activation are suppressed in IFN-γ-primed macrophages by a protein kinase C-dependent pathway following ligation of the IgG Fc gamma receptor [14]. Furthermore, dendritic cells from RA synovial fluids are resistant to the immunoregulatory effect of IL-10 due to decreased transport of intracellular IL-10R1 in the presence of proinflammatory cytokine stimuli such as TNF-α, IL-1, and granulocyte–macrophage colony-stimulating factor [15]. We have demonstrated that the resistance of RA CD4+ T cells to IL-10 may be associated with defective IL-10-dependent STAT3 activation, but not with IL-10R1 expression. Inhibitory effects of IL-10 on these inflammatory cell types are therefore differentially modulated at the signal transduction level under the inflammatory environment in RA."}

{"project":"GO-BP","denotations":[{"id":"T22904","span":{"begin":1608,"end":1620},"obj":"http://purl.obolibrary.org/obo/GO_0009293"},{"id":"T22903","span":{"begin":1158,"end":1167},"obj":"http://purl.obolibrary.org/obo/GO_0006810"},{"id":"T22902","span":{"begin":1601,"end":1620},"obj":"http://purl.obolibrary.org/obo/GO_0007165"},{"id":"T22900","span":{"begin":546,"end":563},"obj":"http://purl.obolibrary.org/obo/GO_0007165"},{"id":"T22899","span":{"begin":474,"end":477},"obj":"http://purl.obolibrary.org/obo/GO_0004707"},{"id":"T22892","span":{"begin":279,"end":298},"obj":"http://purl.obolibrary.org/obo/GO_0001816"}],"text":"Numerous cytokines, both proinflammatory and anti-inflammatory, have been detected in the ST of RA, and the balance between these opposing cytokine activities regulates disease severity [10]. Endogenous IL-10, produced mainly by macrophages and T cells, inhibits proinflammatory cytokine production by ST cells [12]. However, this regulatory activity seems to be restricted during chronic inflammation. The activation of both the extracellular stimulus-regulated kinase and p38 kinase pathways, induced by TNF-α and IL-1, inhibits the Jak1–STAT3 signaling pathway shared by IL-10 and IL-6 in adhered macrophages [13]. More importantly, IL-10-mediated STAT3 activation is mostly undetectable in RA synovial macrophages. This impaired IL-10 signaling is probably induced by chronic exposure to immune complexes in vivo, because both cell surface IL-10R1 expression and IL-10-induced Jak1 activation are suppressed in IFN-γ-primed macrophages by a protein kinase C-dependent pathway following ligation of the IgG Fc gamma receptor [14]. Furthermore, dendritic cells from RA synovial fluids are resistant to the immunoregulatory effect of IL-10 due to decreased transport of intracellular IL-10R1 in the presence of proinflammatory cytokine stimuli such as TNF-α, IL-1, and granulocyte–macrophage colony-stimulating factor [15]. We have demonstrated that the resistance of RA CD4+ T cells to IL-10 may be associated with defective IL-10-dependent STAT3 activation, but not with IL-10R1 expression. Inhibitory effects of IL-10 on these inflammatory cell types are therefore differentially modulated at the signal transduction level under the inflammatory environment in RA."}

{"project":"GO-CC","denotations":[{"id":"T23692","span":{"begin":1171,"end":1184},"obj":"http://purl.obolibrary.org/obo/GO_0005622"},{"id":"T23691","span":{"begin":430,"end":443},"obj":"http://purl.obolibrary.org/obo/GO_0005576"},{"id":"T23667","span":{"begin":1379,"end":1384},"obj":"http://purl.obolibrary.org/obo/GO_0005623"},{"id":"T23666","span":{"begin":1057,"end":1062},"obj":"http://purl.obolibrary.org/obo/GO_0005623"},{"id":"T23665","span":{"begin":305,"end":310},"obj":"http://purl.obolibrary.org/obo/GO_0005623"},{"id":"T23664","span":{"begin":247,"end":252},"obj":"http://purl.obolibrary.org/obo/GO_0005623"}],"text":"Numerous cytokines, both proinflammatory and anti-inflammatory, have been detected in the ST of RA, and the balance between these opposing cytokine activities regulates disease severity [10]. Endogenous IL-10, produced mainly by macrophages and T cells, inhibits proinflammatory cytokine production by ST cells [12]. However, this regulatory activity seems to be restricted during chronic inflammation. The activation of both the extracellular stimulus-regulated kinase and p38 kinase pathways, induced by TNF-α and IL-1, inhibits the Jak1–STAT3 signaling pathway shared by IL-10 and IL-6 in adhered macrophages [13]. More importantly, IL-10-mediated STAT3 activation is mostly undetectable in RA synovial macrophages. This impaired IL-10 signaling is probably induced by chronic exposure to immune complexes in vivo, because both cell surface IL-10R1 expression and IL-10-induced Jak1 activation are suppressed in IFN-γ-primed macrophages by a protein kinase C-dependent pathway following ligation of the IgG Fc gamma receptor [14]. Furthermore, dendritic cells from RA synovial fluids are resistant to the immunoregulatory effect of IL-10 due to decreased transport of intracellular IL-10R1 in the presence of proinflammatory cytokine stimuli such as TNF-α, IL-1, and granulocyte–macrophage colony-stimulating factor [15]. We have demonstrated that the resistance of RA CD4+ T cells to IL-10 may be associated with defective IL-10-dependent STAT3 activation, but not with IL-10R1 expression. Inhibitory effects of IL-10 on these inflammatory cell types are therefore differentially modulated at the signal transduction level under the inflammatory environment in RA."}

{"project":"GO-MF","denotations":[{"id":"T23622","span":{"begin":474,"end":477},"obj":"http://purl.obolibrary.org/obo/GO_0004707"},{"id":"T23621","span":{"begin":139,"end":158},"obj":"http://purl.obolibrary.org/obo/GO_0005125"},{"id":"T23602","span":{"begin":584,"end":588},"obj":"http://purl.obolibrary.org/obo/GO_0005138"},{"id":"T23598","span":{"begin":1260,"end":1264},"obj":"http://purl.obolibrary.org/obo/GO_0005149"},{"id":"T23597","span":{"begin":516,"end":520},"obj":"http://purl.obolibrary.org/obo/GO_0005149"},{"id":"T23573","span":{"begin":1516,"end":1521},"obj":"http://purl.obolibrary.org/obo/GO_0005141"},{"id":"T23572","span":{"begin":1427,"end":1432},"obj":"http://purl.obolibrary.org/obo/GO_0005141"},{"id":"T23571","span":{"begin":1388,"end":1393},"obj":"http://purl.obolibrary.org/obo/GO_0005141"},{"id":"T23570","span":{"begin":1135,"end":1140},"obj":"http://purl.obolibrary.org/obo/GO_0005141"},{"id":"T23569","span":{"begin":867,"end":872},"obj":"http://purl.obolibrary.org/obo/GO_0005141"},{"id":"T23568","span":{"begin":733,"end":738},"obj":"http://purl.obolibrary.org/obo/GO_0005141"},{"id":"T23567","span":{"begin":636,"end":641},"obj":"http://purl.obolibrary.org/obo/GO_0005141"},{"id":"T23566","span":{"begin":574,"end":579},"obj":"http://purl.obolibrary.org/obo/GO_0005141"},{"id":"T23565","span":{"begin":203,"end":208},"obj":"http://purl.obolibrary.org/obo/GO_0005141"}],"text":"Numerous cytokines, both proinflammatory and anti-inflammatory, have been detected in the ST of RA, and the balance between these opposing cytokine activities regulates disease severity [10]. Endogenous IL-10, produced mainly by macrophages and T cells, inhibits proinflammatory cytokine production by ST cells [12]. However, this regulatory activity seems to be restricted during chronic inflammation. The activation of both the extracellular stimulus-regulated kinase and p38 kinase pathways, induced by TNF-α and IL-1, inhibits the Jak1–STAT3 signaling pathway shared by IL-10 and IL-6 in adhered macrophages [13]. More importantly, IL-10-mediated STAT3 activation is mostly undetectable in RA synovial macrophages. This impaired IL-10 signaling is probably induced by chronic exposure to immune complexes in vivo, because both cell surface IL-10R1 expression and IL-10-induced Jak1 activation are suppressed in IFN-γ-primed macrophages by a protein kinase C-dependent pathway following ligation of the IgG Fc gamma receptor [14]. Furthermore, dendritic cells from RA synovial fluids are resistant to the immunoregulatory effect of IL-10 due to decreased transport of intracellular IL-10R1 in the presence of proinflammatory cytokine stimuli such as TNF-α, IL-1, and granulocyte–macrophage colony-stimulating factor [15]. We have demonstrated that the resistance of RA CD4+ T cells to IL-10 may be associated with defective IL-10-dependent STAT3 activation, but not with IL-10R1 expression. Inhibitory effects of IL-10 on these inflammatory cell types are therefore differentially modulated at the signal transduction level under the inflammatory environment in RA."}

{"project":"sentences","denotations":[{"id":"T22821","span":{"begin":1494,"end":1668},"obj":"Sentence"},{"id":"T22820","span":{"begin":1325,"end":1493},"obj":"Sentence"},{"id":"T22819","span":{"begin":1034,"end":1324},"obj":"Sentence"},{"id":"T22818","span":{"begin":719,"end":1033},"obj":"Sentence"},{"id":"T22817","span":{"begin":618,"end":718},"obj":"Sentence"},{"id":"T22816","span":{"begin":403,"end":617},"obj":"Sentence"},{"id":"T22815","span":{"begin":317,"end":402},"obj":"Sentence"},{"id":"T22814","span":{"begin":192,"end":316},"obj":"Sentence"},{"id":"T22813","span":{"begin":0,"end":191},"obj":"Sentence"},{"id":"T156","span":{"begin":0,"end":191},"obj":"Sentence"},{"id":"T157","span":{"begin":192,"end":316},"obj":"Sentence"},{"id":"T158","span":{"begin":317,"end":402},"obj":"Sentence"},{"id":"T159","span":{"begin":403,"end":617},"obj":"Sentence"},{"id":"T160","span":{"begin":618,"end":718},"obj":"Sentence"},{"id":"T161","span":{"begin":719,"end":1033},"obj":"Sentence"},{"id":"T162","span":{"begin":1034,"end":1324},"obj":"Sentence"},{"id":"T163","span":{"begin":1325,"end":1493},"obj":"Sentence"},{"id":"T164","span":{"begin":1494,"end":1668},"obj":"Sentence"}],"namespaces":[{"prefix":"_base","uri":"http://pubannotation.org/ontology/tao.owl#"}],"text":"Numerous cytokines, both proinflammatory and anti-inflammatory, have been detected in the ST of RA, and the balance between these opposing cytokine activities regulates disease severity [10]. Endogenous IL-10, produced mainly by macrophages and T cells, inhibits proinflammatory cytokine production by ST cells [12]. However, this regulatory activity seems to be restricted during chronic inflammation. The activation of both the extracellular stimulus-regulated kinase and p38 kinase pathways, induced by TNF-α and IL-1, inhibits the Jak1–STAT3 signaling pathway shared by IL-10 and IL-6 in adhered macrophages [13]. More importantly, IL-10-mediated STAT3 activation is mostly undetectable in RA synovial macrophages. This impaired IL-10 signaling is probably induced by chronic exposure to immune complexes in vivo, because both cell surface IL-10R1 expression and IL-10-induced Jak1 activation are suppressed in IFN-γ-primed macrophages by a protein kinase C-dependent pathway following ligation of the IgG Fc gamma receptor [14]. Furthermore, dendritic cells from RA synovial fluids are resistant to the immunoregulatory effect of IL-10 due to decreased transport of intracellular IL-10R1 in the presence of proinflammatory cytokine stimuli such as TNF-α, IL-1, and granulocyte–macrophage colony-stimulating factor [15]. We have demonstrated that the resistance of RA CD4+ T cells to IL-10 may be associated with defective IL-10-dependent STAT3 activation, but not with IL-10R1 expression. Inhibitory effects of IL-10 on these inflammatory cell types are therefore differentially modulated at the signal transduction level under the inflammatory environment in RA."}

{"project":"simple1","denotations":[{"id":"T24358","span":{"begin":1516,"end":1521},"obj":"Protein"},{"id":"T24357","span":{"begin":1474,"end":1481},"obj":"Protein"},{"id":"T24356","span":{"begin":1443,"end":1448},"obj":"Protein"},{"id":"T24355","span":{"begin":1427,"end":1432},"obj":"Protein"},{"id":"T24354","span":{"begin":1388,"end":1393},"obj":"Protein"},{"id":"T24353","span":{"begin":1372,"end":1375},"obj":"Protein"},{"id":"T24352","span":{"begin":1270,"end":1318},"obj":"Protein"},{"id":"T24351","span":{"begin":1260,"end":1264},"obj":"Protein"},{"id":"T24350","span":{"begin":1253,"end":1258},"obj":"Protein"},{"id":"T24349","span":{"begin":1185,"end":1192},"obj":"Protein"},{"id":"T24348","span":{"begin":1135,"end":1140},"obj":"Protein"},{"id":"T24347","span":{"begin":915,"end":920},"obj":"Protein"},{"id":"T24346","span":{"begin":881,"end":885},"obj":"Protein"},{"id":"T24345","span":{"begin":867,"end":872},"obj":"Protein"},{"id":"T24344","span":{"begin":844,"end":851},"obj":"Protein"},{"id":"T24343","span":{"begin":733,"end":738},"obj":"Protein"},{"id":"T24342","span":{"begin":651,"end":656},"obj":"Protein"},{"id":"T24341","span":{"begin":636,"end":641},"obj":"Protein"},{"id":"T24340","span":{"begin":584,"end":588},"obj":"Protein"},{"id":"T24339","span":{"begin":574,"end":579},"obj":"Protein"},{"id":"T24338","span":{"begin":540,"end":545},"obj":"Protein"},{"id":"T24337","span":{"begin":535,"end":539},"obj":"Protein"},{"id":"T24336","span":{"begin":516,"end":520},"obj":"Protein"},{"id":"T24335","span":{"begin":506,"end":511},"obj":"Protein"},{"id":"T24334","span":{"begin":203,"end":208},"obj":"Protein"}],"text":"Numerous cytokines, both proinflammatory and anti-inflammatory, have been detected in the ST of RA, and the balance between these opposing cytokine activities regulates disease severity [10]. Endogenous IL-10, produced mainly by macrophages and T cells, inhibits proinflammatory cytokine production by ST cells [12]. However, this regulatory activity seems to be restricted during chronic inflammation. The activation of both the extracellular stimulus-regulated kinase and p38 kinase pathways, induced by TNF-α and IL-1, inhibits the Jak1–STAT3 signaling pathway shared by IL-10 and IL-6 in adhered macrophages [13]. More importantly, IL-10-mediated STAT3 activation is mostly undetectable in RA synovial macrophages. This impaired IL-10 signaling is probably induced by chronic exposure to immune complexes in vivo, because both cell surface IL-10R1 expression and IL-10-induced Jak1 activation are suppressed in IFN-γ-primed macrophages by a protein kinase C-dependent pathway following ligation of the IgG Fc gamma receptor [14]. Furthermore, dendritic cells from RA synovial fluids are resistant to the immunoregulatory effect of IL-10 due to decreased transport of intracellular IL-10R1 in the presence of proinflammatory cytokine stimuli such as TNF-α, IL-1, and granulocyte–macrophage colony-stimulating factor [15]. We have demonstrated that the resistance of RA CD4+ T cells to IL-10 may be associated with defective IL-10-dependent STAT3 activation, but not with IL-10R1 expression. Inhibitory effects of IL-10 on these inflammatory cell types are therefore differentially modulated at the signal transduction level under the inflammatory environment in RA."}

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Endogenous IL-10, produced mainly by macrophages and T cells, inhibits proinflammatory cytokine production by ST cells [12]. However, this regulatory activity seems to be restricted during chronic inflammation. The activation of both the extracellular stimulus-regulated kinase and p38 kinase pathways, induced by TNF-α and IL-1, inhibits the Jak1–STAT3 signaling pathway shared by IL-10 and IL-6 in adhered macrophages [13]. More importantly, IL-10-mediated STAT3 activation is mostly undetectable in RA synovial macrophages. This impaired IL-10 signaling is probably induced by chronic exposure to immune complexes in vivo, because both cell surface IL-10R1 expression and IL-10-induced Jak1 activation are suppressed in IFN-γ-primed macrophages by a protein kinase C-dependent pathway following ligation of the IgG Fc gamma receptor [14]. 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cytokines, both proinflammatory and anti-inflammatory, have been detected in the ST of RA, and the balance between these opposing cytokine activities regulates disease severity [10]. Endogenous IL-10, produced mainly by macrophages and T cells, inhibits proinflammatory cytokine production by ST cells [12]. However, this regulatory activity seems to be restricted during chronic inflammation. The activation of both the extracellular stimulus-regulated kinase and p38 kinase pathways, induced by TNF-α and IL-1, inhibits the Jak1–STAT3 signaling pathway shared by IL-10 and IL-6 in adhered macrophages [13]. More importantly, IL-10-mediated STAT3 activation is mostly undetectable in RA synovial macrophages. This impaired IL-10 signaling is probably induced by chronic exposure to immune complexes in vivo, because both cell surface IL-10R1 expression and IL-10-induced Jak1 activation are suppressed in IFN-γ-primed macrophages by a protein kinase C-dependent pathway following ligation of the IgG Fc gamma receptor [14]. Furthermore, dendritic cells from RA synovial fluids are resistant to the immunoregulatory effect of IL-10 due to decreased transport of intracellular IL-10R1 in the presence of proinflammatory cytokine stimuli such as TNF-α, IL-1, and granulocyte–macrophage colony-stimulating factor [15]. We have demonstrated that the resistance of RA CD4+ T cells to IL-10 may be associated with defective IL-10-dependent STAT3 activation, but not with IL-10R1 expression. Inhibitory effects of IL-10 on these inflammatory cell types are therefore differentially modulated at the signal transduction level under the inflammatory environment in RA."}

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Endogenous IL-10, produced mainly by macrophages and T cells, inhibits proinflammatory cytokine production by ST cells [12]. However, this regulatory activity seems to be restricted during chronic inflammation. The activation of both the extracellular stimulus-regulated kinase and p38 kinase pathways, induced by TNF-α and IL-1, inhibits the Jak1–STAT3 signaling pathway shared by IL-10 and IL-6 in adhered macrophages [13]. More importantly, IL-10-mediated STAT3 activation is mostly undetectable in RA synovial macrophages. This impaired IL-10 signaling is probably induced by chronic exposure to immune complexes in vivo, because both cell surface IL-10R1 expression and IL-10-induced Jak1 activation are suppressed in IFN-γ-primed macrophages by a protein kinase C-dependent pathway following ligation of the IgG Fc gamma receptor [14]. Furthermore, dendritic cells from RA synovial fluids are resistant to the immunoregulatory effect of IL-10 due to decreased transport of intracellular IL-10R1 in the presence of proinflammatory cytokine stimuli such as TNF-α, IL-1, and granulocyte–macrophage colony-stimulating factor [15]. We have demonstrated that the resistance of RA CD4+ T cells to IL-10 may be associated with defective IL-10-dependent STAT3 activation, but not with IL-10R1 expression. Inhibitory effects of IL-10 on these inflammatory cell types are therefore differentially modulated at the signal transduction level under the inflammatory environment in RA."}

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Furthermore, dendritic cells from RA synovial fluids are resistant to the immunoregulatory effect of IL-10 due to decreased transport of intracellular IL-10R1 in the presence of proinflammatory cytokine stimuli such as TNF-α, IL-1, and granulocyte–macrophage colony-stimulating factor [15]. We have demonstrated that the resistance of RA CD4+ T cells to IL-10 may be associated with defective IL-10-dependent STAT3 activation, but not with IL-10R1 expression. Inhibitory effects of IL-10 on these inflammatory cell types are therefore differentially modulated at the signal transduction level under the inflammatory environment in RA."}