Crucial roles of binding sites for NF-κB and C/EBPs in IκB-ζ-mediated transcriptional activation

Matsuo, Susumu; Yamazaki, Soh; Takeshige, Koichiro; Muta, Tsuyoshi

doi:10.1042/bj20061797

Cited by 68 publications

(71 citation statements)

References 46 publications

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“…IκBζ has previously been demonstrated to be highly expressed in Th17 cells, dendritic cells, and macrophages upon TLR stimulation, whereas IκBζ is barely detectable in resting cells (18,31). In agreement with a previous study (10), we found that IκBζ was highly expressed in human keratinocytes upon IL-17A stimulation, whereas TNFα stimulation had only a minor effect on IκBζ expression.…”

Section: Discussionsupporting

confidence: 82%

IκBζ is a key driver in the development of psoriasis

Johansen

Mose

Ommen

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

105

132

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Psoriasis is a common immune-mediated, chronic, inflammatory skin disease characterized by hyperproliferation and abnormal differentiation of keratinocytes and infiltration of inflammatory cells. Although TNFα-and IL-17A-targeting drugs have recently proven to be highly effective, the molecular mechanism underlying the pathogenesis of psoriasis remains poorly understood. We found that expression of the atypical IκB member IκB (inhibitor of NF-κB) ζ, a selective coactivator of particular NF-κB target genes, was strongly increased in skin of patients with psoriasis. Moreover, in human keratinocytes IκBζ was identified as a direct transcriptional activator of TNFα/IL-17A-inducible psoriasis-associated proteins. Using genetically modified mice, we found that imiquimod-induced psoriasis-like skin inflammation was completely absent in IκBζ-deficient mice, whereas skin inflammation was still inducible in IL-17A-and TNFα-deficient mice. IκBζ deficiency also conferred resistance against IL-23-induced psoriasis. In addition, local abrogation of IκBζ function by intradermal injection of IκBζ siRNA abolished psoriasis-like skin inflammation. Taken together, we identify IκBζ as a hitherto unknown key regulator of IL-17A-driven effects in psoriasis. Thus, targeting IκBζ could be a future strategy for treatment of psoriasis, and other inflammatory diseases for which IL-17 antagonists are currently tested in clinical trials.

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Section: Discussionsupporting

confidence: 82%

IκBζ is a key driver in the development of psoriasis

Johansen

Mose

Ommen

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

105

132

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“…Furthermore, overexpression of NFKBIZ in HT1080 cells resulted in elevated IL8 transcription, indicating a role for NFKBIZ. This interpretation is further supported by a recent report showing that NFKBIZ binds and acts on a composite or adjacent C/EBP-NF-kB site almost identical to the site investigated in this study (Matsuo et al, 2007).…”

Section: Fus-ddit3 Deregulates Nf-jb Target Genessupporting

confidence: 91%

The myxoid liposarcoma FUS-DDIT3 fusion oncoprotein deregulates NF-κB target genes by interaction with NFKBIZ

et al. 2008

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FUS (also called TLS), EWSR1 and TAF15 (also called TAF2N) are related genes involved in tumor type-specific fusion oncogenes in human malignancies. The FUS-DDIT3 fusion oncogene results from a t(12;16)(q13;p11) chromosome translocation and has a causative role in the initiation of myxoid/round cell liposarcomas (MLS/ RCLS). The FUS-DDIT3 protein induces increased expression of the CAAT/enhancer-binding protein (C/EBP) and nuclear factor-jB (NF-jB)-controlled gene IL8, and the N-terminal FUS part is required for this activation. Chromatin immunoprecipitation analysis showed that FUS-DDIT3 binds the IL8 promoter. Expression studies of the IL8 promoter harboring a C/EBP-NF-jB composite site pinpointed the importance of NF-jB for IL8 expression in FUS-DDIT3-expressing cells. We therefore probed for possible interaction of FUS-DDIT3 with members of the NF-jB family. The nuclear factor NFKBIZ colocalizes with FUS-DDIT3 in nuclear structures, and immunoprecipitation experiments showed that FUS-DDIT3 binds the C-terminal of NFKBIZ. We also report that additional NF-jB-controlled genes are upregulated at the mRNA level in FUS-DDIT3-expressing cell lines and they can be induced by NFKBIZ. Taken together, the results indicate that FUS-DDIT3 deregulates some NF-jB-controlled genes through interactions with NFKBIZ. Similar mechanisms may be a part of the transformation process in other tumor types carrying FUS, EWSR1 and TAF15 containing fusion oncogenes.

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“…39 Among the genes induced by P. gingivalis LPS is I B␣, which can re-exert control over NF-B, along with I B ⑀ and particularly, I B , which binds to NF-B p50 in the nucleus and has both negative (IL-8, TNF-␣) and positive (IL-6, IL12p40, GM-CSF, G-CSF) regulatory actions. 40,41 Although rapid NF-B activation is necessary for host defense against microbial invasion, failure to re-exert control with persistent NF-B activation may result in tissue injury, and in the extreme, to organ failure, systemic disease, and death. 42,43 NF-B-responsive genes, including abundant chemokines, were up-regulated both transcriptionally and at the protein level, consistent with rapid mobilization and accumulation of innate and/or adaptive immune cells at the site of P. gingivalis infection and release of cell wall components.…”

Section: Discussionmentioning

confidence: 99%

Rapid Myeloid Cell Transcriptional and Proteomic Responses to Periodontopathogenic Porphyromonas gingivalis

Nares

Moutsopoulos

Angelov

et al. 2009

The American Journal of Pathology

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Long-lived monocytes, macrophages, and dendritic cells (DCs) are Toll-like receptor-expressing, antigenpresenting cells derived from a common myeloid lineage that play key roles in innate and adaptive immune responses. Based on immunohistochemical and molecular analyses of inflamed tissues from patients with chronic destructive periodontal disease, these cells, found in the inflammatory infiltrate, may drive the progressive periodontal pathogenesis. To investigate early transcriptional signatures and subsequent proteomic responses to the periodontal pathogen, Porphyromonas gingivalis, donor-matched human blood monocytes, differentiated DCs, and macrophages were exposed to P. gingivalis lipopolysaccharide (LPS) and gene expression levels were measured by oligonucleotide microarrays. In addition to striking differences in constitutive transcriptional profiles between these myeloid populations, we identify a P. gingivalis LPS-inducible convergent, transcriptional core response of more than 400 annotated genes/ESTs among these populations, reflected by a shared, but quantitatively distinct, proteomic response. Nonetheless, clear differences emerged between the monocytes, DCs, and macrophages. The finding that long-lived myeloid inflammatory cells, particularly DCs, rapidly and aggressively respond to P. gingivalis LPS by generating chemokines, proteases, and cytokines capable of driving T-helper cell lineage polarization without evidence of corresponding immunosuppressive pathways highlights their prominent role in host defense and progressive tissue pathogenesis. The shared, unique, and/or complementary transcriptional and proteomic profiles may frame the context of the host response to P. gingivalis, contributing to the destructive nature of periodontal inflammation.

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Crucial roles of binding sites for NF-κB and C/EBPs in IκB-ζ-mediated transcriptional activation

Cited by 68 publications

References 46 publications

IκBζ is a key driver in the development of psoriasis

IκBζ is a key driver in the development of psoriasis

The myxoid liposarcoma FUS-DDIT3 fusion oncoprotein deregulates NF-κB target genes by interaction with NFKBIZ

Rapid Myeloid Cell Transcriptional and Proteomic Responses to Periodontopathogenic Porphyromonas gingivalis

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