Opposing roles of NF-κB family members in the regulation of NK cell proliferation and production of IFN-γ

Department of Medicine, Cornell University, Итак, New York, United States
International Immunology (Impact Factor: 3.18). 05/2006; 18(4):505-13. DOI: 10.1093/intimm/dxh391
Source: PubMed

ABSTRACT It is well established that the nuclear factor-kappaB (NF-kappaB) family of transcription factors participates in the regulation of many aspects of innate and adaptive immunity. The majority of these reports have focused on the role of NF-kappaB in accessory cell and T or B cell function, but less is known about the role of NF-kappaB in NK cells. However, several studies have demonstrated that these transcription factors are required for NK cell production of IFN-gamma and proliferation. The studies presented here examine the role of two NF-kappaB members, c-Rel and p50, in NK cell function. In vitro data revealed that in the absence of c-Rel, NK cells have a defect in their ability to secrete IFN-gamma, but remain unaffected in their capacity to proliferate. In contrast, p50-/- NK cells have enhanced proliferative and IFN-gamma responses compared with wild-type NK cells. The latter findings suggest a role for p50 as a negative regulator of NK cell production of IFN-gamma and chromatin immunoprecipitation assays demonstrated the association of p50 with the IFN-gamma promoter of resting NK cells. Consistent with the in vitro studies, in vivo studies with NF-kappaB gene-deficient mice infected with Toxoplasma gondii revealed that the absence of p50 leads to enhanced NK cell proliferation and production of IFN-gamma. Together, these studies define distinct roles for c-Rel and p50 in the function of NK cells.

  • Source
    • "Although numerous potential NF-κB consensus sites were identified across the Ifng locus, relatively few of these coincided with identified CNSs or HS sites (Fig. S2, and data not shown). Thus, in addition to NF-κB sites previously described (Sica et al., 1997; Tato et al., 2006), highly conserved NF-κB consensus sites were identified in multiple distal CNSs, including CNSs -54, -22, -6, +17, +40, +46 and +54, as well as a tandem site identified in CNS-34 (Fig. S2). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Distal cis-regulatory elements play essential roles in the T lineage-specific expression of cytokine genes. We have mapped interactions of three trans-acting factors-NF-kappaB, STAT4, and T-bet-with cis elements in the Ifng locus. We find that RelA is critical for optimal Ifng expression and is differentially recruited to multiple elements contingent upon T cell receptor (TCR) or interleukin-12 (IL-12) plus IL-18 signaling. RelA recruitment to at least four elements is dependent on T-bet-dependent remodeling of the Ifng locus and corecruitment of STAT4. STAT4 and NF-kappaB therefore cooperate at multiple cis elements to enable NF-kappaB-dependent enhancement of Ifng expression. RelA recruitment to distal elements was similar in T helper 1 (Th1) and effector CD8(+) T (Tc1) cells, although T-bet was dispensable in CD8 effectors. These results support a model of Ifng regulation in which distal cis-regulatory elements differentially recruit key transcription factors in a modular fashion to initiate gene transcription induced by distinct activation signals.
    Immunity 07/2010; 33(1):35-47. DOI:10.1016/j.immuni.2010.07.004 · 19.75 Impact Factor
  • Source
    • "Several immune parameters remained intact or were enhanced in NF-κB1 −/− mice, and thus may contribute to the early control of the parasite. For example, it has been previously reported that NK cells from NF-κB1 −/− mice infected with T. gondii are hyper-proliferative and produce more IFN-γ than their wildtype counterparts (Tato et al., 2006). In addition, the data presented here indicate increased levels of IL-12 are found in the serum of NF-κB1 −/− mice. "
    [Show abstract] [Hide abstract]
    ABSTRACT: In this study, the role of NF-kappaB1 was examined during toxoplasmosis. While wildtype BALB/c mice generated protective responses, NF-kappaB1(-/-) mice developed Toxoplasmic encephalitis, characterized by increased parasite burden and necrosis in the brain. Susceptibility was primarily associated with a local decrease in the number of CD8(+) T cells and IFN-gamma production, while accessory cell function appeared intact in NF-kappaB1(-/-) mice. Consistent with these findings, T cell transfer studies revealed that NF-kappaB1(-/-) T cells provided SCID mice less protection than wildtype T cells. These results demonstrate an intrinsic role for NF-kappaB1 in T cell-mediated immunity to Toxoplasmagondii.
    Journal of neuroimmunology 02/2010; 222(1-2):19-28. DOI:10.1016/j.jneuroim.2009.12.009 · 2.79 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Toxoplasmosis is a widely spread parasitic disease that in most cases persists latently. Immunodeficiency may lead to reactivation of parasite and lethality. As toxoplasma subverts host innate resistance and immunity in this study we evaluated the ability of a range of immunomodulators/inducers of interferons to restore the immune response to the pathogen. Interestingly, we observed that toxoplasma infected mice treated with moraprenil phosphate had less cytopathology in spleen compared to non treated controls that suggested improved protection from infection in the presence of this immunomodulator. Also splenocytes from these mice produced interferons in response to rigostin, cycloferon and morаprenil poshpate. Upregulation of IL-6, IL-10, IL-12, IL-18 mRNA expression was documented. Our data suggest the potential for the therapeutical use of rigostin, cycloferon and moraprenil posphate in treatment of acute toxoplasmosis.
    Meditsinskaia parazitologiia i parazitarnye bolezni
Show more