Critical roles of c-Rel in autoimmune inflammation and helper T cell differentiation

Hilliard, Brendan; Mason, Nicola J.; Xu, Liang; Sun, Jun; Lamhamedi-Cherradi, Salah-Eddine; Liou, Hsiou‐Chi; Hunter, Christopher A.; Chen, Youhai H.

doi:10.1172/jci200215254

Cited by 87 publications

(115 citation statements)

References 32 publications

(10 reference statements)

Supporting

Mentioning

107

Contrasting

Order By: Relevance

“…Consistent with the findings demonstrating that c-Rel regulation of CD4 (Hilliard et al, 2002) and CD8 (Mintern et al, 2002) immune responses is mediated in part through its control of APC function, c-Rel serves a number of roles in different APC. c-rel À/À mice have reduced numbers of plasmacytoid DC (pDC) (O'Keeffe et al, 2005), the major producers of type I IFNs.…”

Section: C-relsupporting

confidence: 84%

“…Despite its ubiquitous expression, the absence of p105 is tolerated during embryonic development and is compatible with neonatal and adult viability (Sha et al, 1995). In addition to a mild learning deficit (Meffert and Baltimore, 2005), loss of NF-kB p50/p105 function is associated with defects in stress responses, Hu et al (1999), Li et al (1999a), Takeda Grumont et al (1998Grumont et al ( , 1999, Cheng et al (2003), Pohl et al (2002) T cells: defects in CD4 and CD8 T-cell responses, Th1 development and cytokine production (IL-2 and GM-CSF) in CD4 + T-cell responses Hilliard et al (2002), Lamhamedi-Cherradi et al (2003), Mason et al (2004), Gerondakis et al (1996), Rao et al (2003) Horwitz et al (1997) rela À/À c-rel À/À Yes (BE13) Multiple hemopoietic defects. Radiation chimeras exhibit nucleated erythrocytes, reduced number of B cells, systemic expansion of granulocytes and a reduction in monocytes Grossmann et al (1999Grossmann et al ( , 2000 T cells exhibit a cell-cycle block early in G1 resulting from a failure to undergo c-Myc-dependent growth Grumont et al (2004) rela À/À c-rel À/ À tnf À/À Neonatal E18 embryos exhibit multiple epidermal defects that include a failure to form specific hair types, disorganized basal Gugasyan et al (2004) Knockout and transgenic models for NF-jB pathway S Gerondakis et al plus impaired innate and adaptive immune function.…”

Section: Nf-kb P50/p105mentioning

confidence: 99%

“…During CD4 þ T-cell responses, c-Rel regulates Th1 development plus quantitative and qualitative aspects of cytokine expression in response to microbial challenge (Mason et al, 2004), in pathogenic models of CNS inflammation (Hilliard et al, 2002), in streptozotocin-induced type I diabetes (Lamhamedi-Cherradi et al, 2003) and during islet allograft rejection (Yang et al, 2002). Whereas c-Reldependent production of IL-12 by professional APC, such as DC (Grumont et al, 2001), has been shown to be important in skewing the development of Th1 responses in experimentally induced EAE (Hilliard et al, 2002), c-Rel function is dispensable for generating Th1 cells and APC-dependent production of IL-12 when challenged with T. gondii (Mason et al, 2004). Instead, the impaired Th1 response seen in c-rel À/À mice infected with T. gondii appears to result from T-cell-intrinsic defects associated with the defective clonal expansion of Th1 effector cells (Mason et al, 2004).…”

Section: C-relmentioning

confidence: 99%

See 2 more Smart Citations

Unravelling the complexities of the NF-κB signalling pathway using mouse knockout and transgenic models

et al. 2006

View full text Add to dashboard Cite

The nuclear factor-jB (NF-jB) signalling pathway serves a crucial role in regulating the transcriptional responses of physiological processes that include cell division, cell survival, differentiation, immunity and inflammation. Here we outline studies using mouse models in which the core components of the NF-jB pathway, namely the IjB kinase subunits (IKKa, IKKb and NEMO), the IjB proteins (IjBa, IjBb, IjBe and Bcl-3) and the five NF-jB transcription factors (NF-jB1, NF-jB2, c-Rel, RelA and RelB), have been genetically manipulated using transgenic and knockout technology.

show abstract

Section: C-relsupporting

confidence: 84%

Section: Nf-kb P50/p105mentioning

confidence: 99%

Section: C-relmentioning

confidence: 99%

See 1 more Smart Citation

Unravelling the complexities of the NF-κB signalling pathway using mouse knockout and transgenic models

et al. 2006

View full text Add to dashboard Cite

show abstract

“…Recent studies have demonstrated that c-Rel is required for the generation of Th1 effector cells (18,28). However, that c-Rel Ϫ/Ϫ mice survive the acute phase of toxoplasmosis suggests that IFN-␥-producing Th1 cells can be generated in the absence of c-Rel and can mediate resistance to T. gondii.…”

Section: C-rel-independent Generation Of Th1 Effector Cellsmentioning

confidence: 99%

“…However, the role of c-Rel in the regulation of Th1 responses is unclear. Recent studies have suggested that c-Rel is intrinsically required by T cells for the production of IFN-␥, and by accessory cells to direct the development of a Th1-type response (18).…”

mentioning

confidence: 99%

T Cell-Intrinsic Expression of c-Rel Regulates Th1 Cell Responses Essential for Resistance toToxoplasma gondii

Mason

Liou

Hunter

2004

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

The ability of many microbial and inflammatory stimuli to activate members of the Rel/NF-κB family of transcription factors is associated with the regulation of innate and adaptive responses required to control infection. Individual family members play distinct roles during different infectious and inflammatory responses. For example, c-Rel is essential for the production of IL-12 in response to LPS, but dispensable for IL-12 production in response to Toxoplasma Ag. To assess the role of c-Rel during immunity to the intracellular pathogen Toxoplasma gondii, wild-type (WT) and c-Rel−/− mice were infected with Toxoplasma and the immune response was analyzed. c-Rel−/− mice developed severe toxoplasmic encephalitis with increased numbers of parasites compared with WT controls and succumbed to infection within 5–8 wk. Although increased susceptibility of c-Rel−/− mice was associated with decreased T cell activation, proliferation, and production of IFN-γ, these mice were able to generate Th1 effector cells that were present in the brain during chronic infection. In vitro mixing studies using WT and c-Rel−/− dendritic cells and WT and c-Rel−/− TCR transgenic T cells indicated that c-Rel−/− dendritic cells are defective in their ability to stimulate T cell responses. However, when c-Rel−/− T cells were transferred into T cell-deficient hosts, early defects in T cell activation, proliferation, and IFN-γ production persisted, and these mice remained susceptible to infection. Together, these studies indicate that although c-Rel is an important regulator of innate immune responses, it also plays an important role in optimization and maintenance of adaptive T cell responses during infection.

show abstract

Distinctions between c‐Rel and other NF‐κB proteins in immunity and disease

Liou

Hsia

2003

BioEssays

Self Cite

View full text Add to dashboard Cite

c-Rel is a proto-oncogene first identified as the cellular counterpart of the v-Rel oncogene derived from the avian reticuloendotheliosis retrovirus (REV-T). It was subsequently discovered that c-Rel belongs to the NF-kappaB/Rel transcription factor family whose members share a common DNA recognition motif and similar signaling pathways. Despite the similarities, however, each NF-kappaB/Rel member possesses unique properties with regard to tissue expression pattern, response to receptor signals and target gene specificity. These differences are fairly evident from the non-redundant phenotypes exhibited by individual NF-kappaB/Rel knockout mice. Hence the work described in this review will compare and contrast the various physiological functions of c-Rel to those of other NF-kappaB members, particularly with respect to the regulation of proliferation, survival and effector functions in multiple hematopoietic and immunological cell types. The study of c-Rel knockout mice in several disease models will also be discussed as they reveal an important role for c-Rel in response to allergens, auto-antigens, allo-antigens and pathogenic infection.

show abstract

Critical roles of c-Rel in autoimmune inflammation and helper T cell differentiation

Cited by 87 publications

References 32 publications

Unravelling the complexities of the NF-κB signalling pathway using mouse knockout and transgenic models

Unravelling the complexities of the NF-κB signalling pathway using mouse knockout and transgenic models

T Cell-Intrinsic Expression of c-Rel Regulates Th1 Cell Responses Essential for Resistance toToxoplasma gondii

Distinctions between c‐Rel and other NF‐κB proteins in immunity and disease

Contact Info

Product

Resources

About