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PubMed: 25681350

Title
RelB/p50 complexes regulate cytokine-induced YKL-40 expression.
Journal
Journal of immunology (Baltimore, Md. : 1950)
Volume
194
Issue
None
Pages
2862-70
Date
2015-03-15
Authors
Bhardwaj R | Biswas DD | Boyce BF | Hauser KF | Kordula T | Singh SK | Surace MJ | Waters MR | Yao Z | Yester JW

Evidence 82f4064ee8
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Indeed, YKL-40 mRNA expression was robustly activated in tissues surrounding the site of turpentine injection and its induction was accompanied by a very strong induction of both IL-1 and IL-6 mRNAs (Fig. 1A)

a(PUBCHEM:14235) increases r(MGI:"chitinase-like 1") View Subject | View Object

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r(MGI:"chitinase-like 1") positiveCorrelation r(MGI:"interleukin 1 alpha") View Subject | View Object

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r(MGI:"chitinase-like 1") positiveCorrelation r(MGI:"interleukin 6") View Subject | View Object

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r(MGI:"interleukin 1 alpha") positiveCorrelation r(MGI:"chitinase-like 1") View Subject | View Object

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r(MGI:"interleukin 6") positiveCorrelation r(MGI:"chitinase-like 1") View Subject | View Object

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Evidence f6e0d5d386
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RelB mRNA expression was also strongly activated in vivo by turpentine in an IL-1-dependent model of irritant-induced sterile inflammation (Fig. 4E).

a(PUBCHEM:14235) increases r(MGI:"avian reticuloendotheliosis viral (v-rel) oncogene related B") View Subject | View Object

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Evidence 0588af4c5c
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Since p65 subunit of NF-κB and STAT3 were previously implicated in cytokine-induced expression of YKL-40 (8, 34), we knocked down their expression in human astrocytes

p(MGI:"chitinase-like 1") association p(MGI:"v-rel reticuloendotheliosis viral oncogene homolog A (avian)") View Subject | View Object

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p(MGI:"chitinase-like 1") association p(MGI:"signal transducer and activator of transcription 3") View Subject | View Object

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p(MGI:"signal transducer and activator of transcription 3") association p(MGI:"chitinase-like 1") View Subject | View Object

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p(MGI:"v-rel reticuloendotheliosis viral oncogene homolog A (avian)") association p(MGI:"chitinase-like 1") View Subject | View Object

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Evidence 02c68e2f95
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Surprisingly, knockdown of p65 had no effect on YKL-40 mRNA expression (Fig. 3A), but did drastically diminish the expression of IL-8 mRNA, which is p65-dependent (Fig. 3B).

p(MGI:"chitinase-like 1") association p(MGI:"v-rel reticuloendotheliosis viral oncogene homolog A (avian)") View Subject | View Object

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p(MGI:"v-rel reticuloendotheliosis viral oncogene homolog A (avian)") association p(MGI:"chitinase-like 1") View Subject | View Object

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p(MGI:"v-rel reticuloendotheliosis viral oncogene homolog A (avian)") decreases p(MGI:"chemokine (C-X-C motif) ligand 15") View Subject | View Object

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Evidence 3a795fe85c
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Knockdown of either RelB or p50 significantly diminished cytokine-induced YKL-40 mRNA expression, whereas knockdown of p65, cRel and p52 had no effect (Fig. 4A). This finding implicates both RelB and p50 in YKL-40 regulation.

p(MGI:"chitinase-like 1") association p(MGI:"v-rel reticuloendotheliosis viral oncogene homolog A (avian)") View Subject | View Object

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p(MGI:"chitinase-like 1") association p(MGI:"reticuloendotheliosis oncogene") View Subject | View Object

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p(MGI:"chitinase-like 1") association p(MGI:"nuclear factor of kappa light polypeptide gene enhancer in B cells 2, p49/p100") View Subject | View Object

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p(MGI:"avian reticuloendotheliosis viral (v-rel) oncogene related B") increases r(MGI:"chitinase-like 1") View Subject | View Object

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p(MGI:"avian reticuloendotheliosis viral (v-rel) oncogene related B") regulates p(MGI:"chitinase-like 1") View Subject | View Object

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p(MGI:"nuclear factor of kappa light polypeptide gene enhancer in B cells 1, p105") increases r(MGI:"chitinase-like 1") View Subject | View Object

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p(MGI:"nuclear factor of kappa light polypeptide gene enhancer in B cells 1, p105") regulates p(MGI:"chitinase-like 1") View Subject | View Object

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p(MGI:"nuclear factor of kappa light polypeptide gene enhancer in B cells 2, p49/p100") association p(MGI:"chitinase-like 1") View Subject | View Object

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p(MGI:"reticuloendotheliosis oncogene") association p(MGI:"chitinase-like 1") View Subject | View Object

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p(MGI:"v-rel reticuloendotheliosis viral oncogene homolog A (avian)") association p(MGI:"chitinase-like 1") View Subject | View Object

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Evidence b3bf096fb2
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Cytokine stimulation facilitated the binding of protein complexes to the proximal NF-κB element in vitro, which super-shifted with anti-p65, anti-RelB and anti-p50 antibodies (Fig. 5D), indicating that the proximal NF-κB site can bind both p65/p50 and RelB/p50 complexes.

p(MGI:"chitinase-like 1") increases complex(p(MGI:"avian reticuloendotheliosis viral (v-rel) oncogene related B"), p(MGI:"chitinase-like 1"), p(MGI:"nuclear factor of kappa light polypeptide gene enhancer in B cells 1, p105")) View Subject | View Object

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p(MGI:"chitinase-like 1") increases complex(a(GO:"NF-kappaB p50/p65 complex"), p(MGI:"chitinase-like 1")) View Subject | View Object

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Evidence 0d4caaf2a2
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These data suggests that RelB regulates expression of YKL-40 in response to proinflammatory cytokines, such as IL-1 and TNF, which induce canonical activation of RelB/p50 complexes.

p(MGI:"avian reticuloendotheliosis viral (v-rel) oncogene related B") regulates p(MGI:"chitinase-like 1") View Subject | View Object

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p(MGI:"interleukin 1 alpha") increases act(p(MGI:"avian reticuloendotheliosis viral (v-rel) oncogene related B")) View Subject | View Object

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p(MGI:"interleukin 1 alpha") increases act(complex(p(MGI:"avian reticuloendotheliosis viral (v-rel) oncogene related B"), p(MGI:"nuclear factor of kappa light polypeptide gene enhancer in B cells 1, p105"))) View Subject | View Object

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p(MGI:"tumor necrosis factor") increases act(p(MGI:"avian reticuloendotheliosis viral (v-rel) oncogene related B")) View Subject | View Object

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p(MGI:"tumor necrosis factor") increases act(complex(p(MGI:"avian reticuloendotheliosis viral (v-rel) oncogene related B"), p(MGI:"nuclear factor of kappa light polypeptide gene enhancer in B cells 1, p105"))) View Subject | View Object

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Evidence f3f03e314d
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Cumulatively, these data suggest that in cells expressing relatively low levels of YKL-40, such as astrocytes, cytokine-driven RelB promotes YKL-40 induction in vitro and in vivo.

p(MGI:"avian reticuloendotheliosis viral (v-rel) oncogene related B") increases p(MGI:"chitinase-like 1") View Subject | View Object

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Cell Ontology (CL)
astrocyte

Evidence 7efd5e4535
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These experiments were performed in U373 glioma cells, which similarly to human and mouse astrocytes, upregulate expression of both YKL-40 and RelB in response to IL-1 and OSM, and this cytokine-induced expression is diminished by the knockdown of p50 and RelB (Suppl. Fig. 4).

p(MGI:"avian reticuloendotheliosis viral (v-rel) oncogene related B") increases act(p(MGI:"interleukin 1 alpha")) View Subject | View Object

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p(MGI:"avian reticuloendotheliosis viral (v-rel) oncogene related B") increases act(p(MGI:"oncostatin M")) View Subject | View Object

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p(MGI:"nuclear factor of kappa light polypeptide gene enhancer in B cells 1, p105") increases act(p(MGI:"interleukin 1 alpha")) View Subject | View Object

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p(MGI:"nuclear factor of kappa light polypeptide gene enhancer in B cells 1, p105") increases act(p(MGI:"oncostatin M")) View Subject | View Object

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p(MGI:"interleukin 1 alpha") increases path(MESH:Glioblastoma) View Subject | View Object

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p(MGI:"oncostatin M") increases path(MESH:Glioblastoma) View Subject | View Object

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path(MESH:Glioblastoma) increases p(MGI:"chitinase-like 1") View Subject | View Object

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path(MESH:Glioblastoma) increases p(MGI:"avian reticuloendotheliosis viral (v-rel) oncogene related B") View Subject | View Object

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Evidence 3aab05c401
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Although RelB and p50 did not bind to the YKL-40 promoter in unstimulated U373 cells, binding of RelB and p50 was apparent in cytokine-treated cells (Fig. 5B), suggesting that RelB/p50 complexes directly regulate YKL-40 expression.

complex(p(MGI:"avian reticuloendotheliosis viral (v-rel) oncogene related B"), p(MGI:"nuclear factor of kappa light polypeptide gene enhancer in B cells 1, p105")) regulates p(MGI:"chitinase-like 1") View Subject | View Object

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Evidence 4185614ece
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We conclude that RelB/p50 complexes can directly bind to the proximal NF-κB site of the YKL-40 promoter and are essential for the cytokine-induced YKL-40 expression.

complex(p(MGI:"avian reticuloendotheliosis viral (v-rel) oncogene related B"), p(MGI:"nuclear factor of kappa light polypeptide gene enhancer in B cells 1, p105")) increases p(MGI:"chitinase-like 1") View Subject | View Object

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complex(p(MGI:"avian reticuloendotheliosis viral (v-rel) oncogene related B"), p(MGI:"nuclear factor of kappa light polypeptide gene enhancer in B cells 1, p105")) increases complex(p(MGI:"avian reticuloendotheliosis viral (v-rel) oncogene related B"), p(MGI:"chitinase-like 1"), p(MGI:"nuclear factor of kappa light polypeptide gene enhancer in B cells 1, p105")) View Subject | View Object

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Evidence 45477ce781
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These data suggest that in addition to STAT3 activation, OSM enhances YKL-40 expression by promoting formation of the RelB/p50 complexes, which bind to the YKL-40 promoter

complex(p(MGI:"avian reticuloendotheliosis viral (v-rel) oncogene related B"), p(MGI:"nuclear factor of kappa light polypeptide gene enhancer in B cells 1, p105")) increases complex(p(MGI:"avian reticuloendotheliosis viral (v-rel) oncogene related B"), p(MGI:"chitinase-like 1"), p(MGI:"nuclear factor of kappa light polypeptide gene enhancer in B cells 1, p105")) View Subject | View Object

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p(MGI:"oncostatin M") increases act(p(MGI:"signal transducer and activator of transcription 3")) View Subject | View Object

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p(MGI:"oncostatin M") increases p(MGI:"chitinase-like 1") View Subject | View Object

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p(MGI:"oncostatin M") increases complex(p(MGI:"avian reticuloendotheliosis viral (v-rel) oncogene related B"), p(MGI:"nuclear factor of kappa light polypeptide gene enhancer in B cells 1, p105")) View Subject | View Object

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Evidence 120e7df30c
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In agreement with the mutational analysis that showed the importance of the proximal NF-κB site (Fig. 3D), strong protein binding to the proximal, but not distal, NF-κB site of the YKL-40 promoter was induced by IL-1 alone or together with OSM (Fig. 5C).

composite(p(MGI:"interleukin 1 alpha"), p(MGI:"oncostatin M")) increases complex(p(MGI:"avian reticuloendotheliosis viral (v-rel) oncogene related B"), p(MGI:"chitinase-like 1"), p(MGI:"nuclear factor of kappa light polypeptide gene enhancer in B cells 1, p105")) View Subject | View Object

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p(MGI:"interleukin 1 alpha") increases complex(p(MGI:"avian reticuloendotheliosis viral (v-rel) oncogene related B"), p(MGI:"chitinase-like 1"), p(MGI:"nuclear factor of kappa light polypeptide gene enhancer in B cells 1, p105")) View Subject | View Object

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Evidence da1efc5a98
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NF-κB and STAT3 are the major transcription factors activated by IL-1 and OSM, respectively

p(MGI:"interleukin 1 alpha") increases complex(GO:"NF-kappaB complex") View Subject | View Object

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p(MGI:"interleukin 1 alpha") increases p(MGI:"signal transducer and activator of transcription 3") View Subject | View Object

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p(MGI:"oncostatin M") increases complex(GO:"NF-kappaB complex") View Subject | View Object

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p(MGI:"oncostatin M") increases p(MGI:"signal transducer and activator of transcription 3") View Subject | View Object

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Evidence 25d4e011eb
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OSM and IL-1 efficiently regulated YKL-40 expression via STAT3 (Fig. 3A) and OSM promoted the recruitment of IL-1-induced p50 to the YKL-40 promoter (Fig. 5B).

p(MGI:"interleukin 1 alpha") increases act(p(MGI:"signal transducer and activator of transcription 3")) View Subject | View Object

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p(MGI:"interleukin 1 alpha") regulates p(MGI:"chitinase-like 1") View Subject | View Object

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p(MGI:"interleukin 1 alpha") increases p(MGI:"nuclear factor of kappa light polypeptide gene enhancer in B cells 1, p105") View Subject | View Object

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p(MGI:"oncostatin M") increases act(p(MGI:"signal transducer and activator of transcription 3")) View Subject | View Object

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p(MGI:"oncostatin M") regulates p(MGI:"chitinase-like 1") View Subject | View Object

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p(MGI:"oncostatin M") increases complex(p(MGI:"chitinase-like 1"), p(MGI:"nuclear factor of kappa light polypeptide gene enhancer in B cells 1, p105")) View Subject | View Object

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p(MGI:"signal transducer and activator of transcription 3") increases p(MGI:"chitinase-like 1") View Subject | View Object

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Evidence fc6deecc93
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Downregulation of STAT3 (Fig. 3C) dramatically diminished IL-1/OSM-induced YKL-40 mRNA expression (Fig. 3A).

p(MGI:"interleukin 1 alpha") increases r(MGI:"chitinase-like 1") View Subject | View Object

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p(MGI:"oncostatin M") increases r(MGI:"chitinase-like 1") View Subject | View Object

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p(MGI:"signal transducer and activator of transcription 3") increases r(MGI:"chitinase-like 1") View Subject | View Object

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Evidence cefa7c9eab
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Similarly, RelB mRNA expression was also up-regulated by IL-1 in mouse astrocytes (Fig. 4D).

p(MGI:"interleukin 1 alpha") increases r(MGI:"avian reticuloendotheliosis viral (v-rel) oncogene related B") View Subject | View Object

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Cell Ontology (CL)
astrocyte

Evidence c825ede45d
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Indeed, p50/RelB complexes were formed in response to IL-1

p(MGI:"interleukin 1 alpha") increases complex(p(MGI:"avian reticuloendotheliosis viral (v-rel) oncogene related B"), p(MGI:"nuclear factor of kappa light polypeptide gene enhancer in B cells 1, p105")) View Subject | View Object

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Evidence 97167d924c
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More importantly, OSM significantly enhanced IL-1-induced formation of the p50/RelB complexes

act(p(MGI:"interleukin 1 alpha")) increases complex(p(MGI:"avian reticuloendotheliosis viral (v-rel) oncogene related B"), p(MGI:"nuclear factor of kappa light polypeptide gene enhancer in B cells 1, p105")) View Subject | View Object

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p(MGI:"oncostatin M") increases act(p(MGI:"interleukin 1 alpha")) View Subject | View Object

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Evidence 22a80fa6be
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Interestingly, although human astrocytes constitutively express low levels of RelB, IL-1 induced dramatic RelB protein accumulation in these cells (Fig. 4C).

p(HGNC:IL1A) increases p(HGNC:RELB) View Subject | View Object

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Cell Ontology (CL)
astrocyte

Evidence 26f9e91938
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In contrast to astrocytes and U373 cells, we found that basal expression of YKL-40 and RelB mRNA was very high in primary human chondrocytes and not stimulated by IL-1 or OSM (Supplementary Fig 3).

p(HGNC:IL1A) causesNoChange r(HGNC:CHI3L1) View Subject | View Object

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Cell Ontology (CL)
chondrocyte

p(HGNC:IL1A) causesNoChange r(HGNC:RELB) View Subject | View Object

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Cell Ontology (CL)
chondrocyte

p(HGNC:OSM) causesNoChange r(HGNC:CHI3L1) View Subject | View Object

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Cell Ontology (CL)
chondrocyte

p(HGNC:OSM) causesNoChange r(HGNC:RELB) View Subject | View Object

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Cell Ontology (CL)
chondrocyte

Evidence fbda790576
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In these cells, basal expression of YKL-40 is RelB-, p65-, and STAT3-independent, implicating other unknown factors.

p(HGNC:RELA) causesNoChange p(HGNC:CHI3L1) View Subject | View Object

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Cell Ontology (CL)
chondrocyte

p(HGNC:RELB) causesNoChange p(HGNC:CHI3L1) View Subject | View Object

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Cell Ontology (CL)
chondrocyte

p(HGNC:STAT3) causesNoChange p(HGNC:CHI3L1) View Subject | View Object

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Cell Ontology (CL)
chondrocyte

Evidence 39f16f142c
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Immunization of mice with MOG35-50 peptide resulted in the induction of EAE, and modest upregulation of YKL-40 mRNA expression in the spinal cords of animals (Fig. 1B).

p(MGI:"myelin oligodendrocyte glycoprotein", frag("35_50")) increases r(MGI:"chitinase-like 1") View Subject | View Object

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MeSH
Spinal Cord

Evidence 5d1143458a
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In addition, expression of both IL-1 and IL-6 mRNAs was also enhanced

p(MGI:"myelin oligodendrocyte glycoprotein", frag("35_50")) increases r(MGI:"interleukin 1 alpha") View Subject | View Object

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p(MGI:"myelin oligodendrocyte glycoprotein", frag("35_50")) increases r(MGI:"interleukin 6") View Subject | View Object

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Evidence a880234801
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Constitutively active STAT3 enhanced, whereas dominant-negative IκBα diminished cytokine-responsiveness.

p(MGI:"nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor, alpha", var("?")) decreases act(p(MGI:"interleukin 1 alpha")) View Subject | View Object

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p(MGI:"nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor, alpha", var("?")) decreases act(p(MGI:"oncostatin M")) View Subject | View Object

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act(p(MGI:"signal transducer and activator of transcription 3")) increases act(p(MGI:"interleukin 1 alpha")) View Subject | View Object

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act(p(MGI:"signal transducer and activator of transcription 3")) increases act(p(MGI:"oncostatin M")) View Subject | View Object

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Evidence d2e90d5b3e
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Since TNF also efficiently activates NF-κB, we tested whether, similarly to IL-1, TNF regulates YKL-40 expression by a RelB-dependent mechanism.

p(MGI:"tumor necrosis factor") increases act(complex(GO:"NF-kappaB complex")) View Subject | View Object

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