Defective Lymphotoxin-β Receptor-Induced NF-κB Transcriptional Activity in NIK-Deficient Mice

Li, Yin; Wu, Lin; Wesche, Holger; Arthur, Cora D.; White, J. Michael; Goeddel, David V.; Schreiber, Robert D.

doi:10.1126/science.1058453

Cited by 388 publications

(341 citation statements)

References 22 publications

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“…2A). Consistent to this proposal, nik -/-MEF displayed defects in NF-κB/ RelA dependent gene expression during LTβR signaling (Yin et al, 2001). Similarly, signals transduced through CD40R and BAFFR that control B-cell maturation were also shown to utilize the NIK pathway for RelA activation (Ramakrishnan et al, 2004).…”

Section: Mapping Rela:p50 Dimer Activation Pathway Downstream Of Ltβrmentioning

confidence: 65%

Crosstalk via the NF-κB signaling system

Basak¹,

Hoffmann²

2008

Cytokine & Growth Factor Reviews

155

117

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The NF-κB family of transcription factors consists of fifteen possible dimers whose activity is controlled by a family of inhibitor proteins, known as IκBs. A variety of cellular stimuli, many of them transduced by members of the TNFR superfamily, induce degradation of IκBs to activate an overlapping subset of NF-κB dimers. However, generation and stimulus-responsive activation of NF-κB dimers are intimately linked via various cross-regulatory mechanisms that allow crosstalk between different signaling pathways through the NF-κB signaling system. In this review, we summarize these mechanisms and discuss physiological and pathological consequences of crosstalk between apparently distinct inflammatory and developmental signals. We argue that a systems approach will be valuable for understanding questions of specificity and emergent properties of highly networked cellular signaling systems.

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Section: Mapping Rela:p50 Dimer Activation Pathway Downstream Of Ltβrmentioning

confidence: 65%

Crosstalk via the NF-κB signaling system

Basak¹,

Hoffmann²

2008

Cytokine & Growth Factor Reviews

155

117

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“…NIK was originally identified as a kinase required for NF-B activation induced by a wide variety of ligand binding (2). It is now clear, however, that the requirement for NIK for NF-B activation is strictly signal-dependent; NF-B activation induced by TNF-␣ takes place without NIK, whereas NIK is essential for NF-B activation downstream of the LT␤R (7,33). The NIKrelated signaling pathway(s) involved in the establishment of self-tolerance in a thymic-stroma dependent fashion are presently unknown.…”

Section: Discussionmentioning

confidence: 99%

NF-κB-Inducing Kinase Establishes Self-Tolerance in a Thymic Stroma-Dependent Manner

Kajiura¹,

Sun²,

Nomura

et al. 2004

The Journal of Immunology

198

225

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Physical contact between thymocytes and the thymic stroma is essential for T cell maturation and shapes the T cell repertoire in the periphery. Stromal elements that control these processes still remain elusive. We used a mouse strain with mutant NF-κB-inducing kinase (NIK) to examine the mechanisms underlying the breakdown of self-tolerance. This NIK-mutant strain manifests autoimmunity and disorganized thymic structure with abnormal expression of Rel proteins in the stroma. Production of immunoregulatory T cells that control autoreactive T cells was impaired in NIK-mutant mice. The autoimmune disease seen in NIK-mutant mice was reproduced in athymic nude mice by grafting embryonic thymus from NIK-mutant mice, and this was rescued by supply of exogenous immunoregulatory T cells. Impaired production of immunoregulatory T cells by thymic stroma without normal NIK was associated with altered expression of peripheral tissue-restricted Ags, suggesting an essential role of NIK in the thymic microenvironment in the establishment of central tolerance.

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“…In addition, our findings suggest significant differences in LPS signaling between macrophages and endothelial cells or fibroblasts. A possible reason for the discrepancy in these data is that, as for nuclear factor B-inducing kinase (NIK), there is a different usage of signaling components between transformed cell lines (e.g., THP-1 cells), where cell proliferation is the essential process, and primary cells such as macrophages, which do not divide (42,61,62). However, in the case of IKK-2, the situation appears more subtle, since IKK-2 is also involved in LPS signaling in primary cells, such as HUVECs and synovial fibroblasts.…”

Section: Discussionmentioning

confidence: 99%

Heterogeneous requirement of IκB kinase 2 for inflammatory cytokine and matrix metalloproteinase production in rheumatoid arthritis: Implications for therapy

Andreakos¹,

Smith²,

Kiriakidis³

et al. 2003

Arthritis & Rheumatism

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Objective. To investigate the potential role of I B kinase 1 (IKK-1) and IKK-2 in the regulation of nuclear factor B (NF-B) activation and the expression of tumor necrosis factor ␣ (TNF␣), as well as interleukin-1␤ (IL-1␤), IL-6, IL-8, vascular endothelial growth factor (VEGF), and matrix metalloproteinases (MMPs), in rheumatoid arthritis (RA).Methods. Recombinant adenoviruses expressing ␤-galactosidase, dominant-negative IKK-1 and IKK-2, or I B␣ were used to infect ex vivo RA synovial membrane cultures and synovial fibroblasts obtained from patients with RA undergoing joint replacement surgery, or human dermal fibroblasts, human umbilical vein endothelialcells(HUVECs),andmonocyte-derivedmacrophages from healthy volunteers. Then, their effect on the spontaneous or stimulus-induced release of inflammatory cytokines, VEGF, and MMPs from RA synovial membrane cells was examined.Results. IKK-2 was not required for lipopolysaccharide (LPS)-induced NF-B activation or TNF␣, IL-6, or IL-8 production in macrophages, but was essential for this process in response to CD40 ligand,

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Defective Lymphotoxin-β Receptor-Induced NF-κB Transcriptional Activity in NIK-Deficient Mice

Cited by 388 publications

References 22 publications

Crosstalk via the NF-κB signaling system

Crosstalk via the NF-κB signaling system

NF-κB-Inducing Kinase Establishes Self-Tolerance in a Thymic Stroma-Dependent Manner

Heterogeneous requirement of IκB kinase 2 for inflammatory cytokine and matrix metalloproteinase production in rheumatoid arthritis: Implications for therapy

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