IκBζ is essential for natural killer cell activation in response to IL-12 and IL-18

Miyake, Toru; Satoh, Takashi; Kato, Hiroki; Matsushita, Kazunobu; Kumagai, Yutaro; Vandenbon, Alexis; Tani, Tohru; Muta, Tsuyoshi; Akira, Shizuo; Takeuchi, Osamu

doi:10.1073/pnas.1012977107

Cited by 49 publications

(48 citation statements)

References 35 publications

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“…However, after our manuscript received its initial review, a similar finding in murine NK cells was submitted and published. 39 As described here in humans, this work demonstrates the role of IB in IFN-␥ production in murine NK cells in response to IL-12 and IL-18. Importantly, the murine work documents the significant role that IB plays in host defense against murine cytomegalovirus infections.…”

Section: Discussionmentioning

confidence: 62%

IκBζ augments IL-12– and IL-18–mediated IFN-γ production in human NK cells

Kannan

Raices

et al. 2011

Blood

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Interferon-γ (IFN-γ) production by natural killer (NK) cells and cytotoxic lymphocytes is a key component of innate and adaptive immune responses. Because inhibitor of κB-ζ (IκBζ), a Toll-like receptor (TLR)/interleukin-1 receptor (IL-1R) inducible transcription factor, regulates IFN-γ production in KG-1 cells, we tested IκBζ's role in the classic lymphocyte pathway of IL-12/IL-18–induced IFN-γ. Upon stimulation with IL-12/IL-18, monocyte-depleted human peripheral blood lymphocytes expressed the 79-kDa form of IκBζ and released IFN-γ. CD56+ NK cells were shown to be the IκBζ-producing lymphocyte subpopulation, which also released abundant IFN-γ in response to IL-12/IL-18. Importantly, IκBζ was undetectable in CD56− lymphocytes where IFN-γ release was 10-fold lower. In addition, small interfering RNA knockdown of IκBζ suppressed IFN-γ expression in CD56+ cells. The association of IκBζ with the IFN-γ promoter was documented by chromatin immunoprecipitation. IFN-γ promoter activity from IκBζ overexpression was confirmed by luciferase reporter assay. Finally, IκBζ coprecipitated with p65 and p50 NF-κB in NK cells in response to IL-12/IL-18, suggesting that IκBζ's effects on IFN-γ promoter activity are coregulated by NF-κB. These results suggest that IκBζ functions as an important regulator of IFN-γ in human NK cells, further expanding the class of IκBζ-modulated genes.

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Section: Discussionmentioning

confidence: 62%

IκBζ augments IL-12– and IL-18–mediated IFN-γ production in human NK cells

Kannan

Raices

et al. 2011

Blood

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“…Engagement of TLR2 may enhance IFNγ secretion through the activation of NF-kB and Ik-Bzeta, similarly to IL-18R activation (Akira et al, 2006). The late increase of HCMV-dependent IFNγ mRNA levels is reminiscent of the kinetics of IFNγ production upon IL-12+IL-18 stimulation in NK cells (Miyake et al, 2010; Kannan et al, 2011). Of note, two genetic studies have shown that specific TLR2 polymorphisms condition the probability to develop CMV disease in transplant recipients (Kijpittayarit et al, 2007; Kang et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Priming of NK Cell Anti-Viral Effector Mechanisms by Direct Recognition of Human Cytomegalovirus

Muntasell¹,

Costa‐García²,

Vera³

et al. 2013

Front. Immun.

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Natural killer (NK) cells play an important role in the defense against viral infections. Activation of resting NK cells is tightly controlled by the balance of surface inhibitory and activating receptors and aided by cytokines released by accessory cells along the anti-viral response. On the other hand, NK cells express functional pattern recognition receptors (PRRs) whose function has been mostly addressed by the use of synthetic agonists. The present study was undertaken to investigate whether NK cells could directly recognize a complex pathogen such as Human Cytomegalovirus (HCMV). Exposure of primary human NK cells to HCMV (TB40/E strain) induced the expression of CD69, promoted IFNγ secretion, and increased their cytotoxic activity against HCMV-infected autologous monocyte-derived dendritic cells. The divergent response induced by infective and UV-inactivated virions indicated the involvement of different NK cell sensors in the recognition of HCMV. The fact that NK cell activation could be partially prevented by blocking mAb specific for IFNAR and TLR2, together with the induction of IFNβ mRNA, supported the involvement of IFNβ and TLR2 in the response to HCMV. Thus, our data indicate that simultaneous activation of several PRRs leads to the autonomous priming of NK cell effector functions and could be a previously unappreciated mechanism presumably contributing to the control of HCMV infection.

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“…This gene has been shown to have several functions, including roles in natural killer cell activation 31 and monocyte recruitment 32. Recently, however, NFKBIZ has also been shown to be a critical regulator of Th17 development through its interaction with ROR nuclear receptors 33.…”

Section: Box: Selected Candidate Genes In the Newly-associated Ibd Sumentioning

confidence: 99%

Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations

et al. 2015

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Ulcerative colitis and Crohn’s disease are the two main forms of inflammatory bowel disease (IBD). Here, we report the first trans-ethnic association study of IBD, with genome-wide or Immunochip genotype data from an extended cohort of 86,640 European individuals and Immunochip data from 9,846 individuals of East-Asian, Indian or Iranian descent. We implicate 38 loci in IBD risk for the first time. For the majority of IBD risk loci, the direction and magnitude of effect is consistent in European and non-European cohorts. Nevertheless, we observe genetic heterogeneity between divergent populations at several established risk loci driven by a combination of differences in allele frequencies (NOD2), effect sizes (TNFSF15, ATG16L1) or a combination of both (IL23R, IRGM). Our results provide biological insights into the pathogenesis of IBD, and demonstrate the utility of trans-ethnic association studies for mapping complex disease loci and understanding genetic architecture across diverse populations.

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IκBζ is essential for natural killer cell activation in response to IL-12 and IL-18

Cited by 49 publications

References 35 publications

IκBζ augments IL-12– and IL-18–mediated IFN-γ production in human NK cells

IκBζ augments IL-12– and IL-18–mediated IFN-γ production in human NK cells

Priming of NK Cell Anti-Viral Effector Mechanisms by Direct Recognition of Human Cytomegalovirus

Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations

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