The nervous system and innate immunity: the neuropeptide connection

Brogden, Kim A.; Guthmiller, Janet M.; Salzet, Michel; Zasloff, Michael

doi:10.1038/ni1209

Cited by 431 publications

(363 citation statements)

References 104 publications

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“…In a recent study, treatment with Jagged1-and Delta1-Fc fusion proteins differentially modulated the course of EAE (27). With ␥-secretase inhibitors, it has been shown that blocking the Notch pathway prevents Th1 polarization and IFN-␥ secretion (15). Administration of GSI in vivo delayed the onset of EAE and substantially reduced clinical signs (15).…”

Section: Discussionmentioning

confidence: 99%

Notch3 Inhibition in Myelin-Reactive T Cells Down-Regulates Protein Kinase Cθ and Attenuates Experimental Autoimmune Encephalomyelitis

Juryńczyk

Jurewicz

Raine

et al. 2008

The Journal of Immunology

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Among its varied functions, Notch signaling is involved in peripheral T cells responses. The activation and polarization of CD4+ T cells toward a Th1 lineage are essential steps in the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis. Inhibition of all four Notch receptors with a γ-secretase inhibitor was shown to block Th1-type polarization and to attenuate the symptoms of experimental autoimmune encephalomyelitis. In this study, we have examined the role of individual Notch receptors in proliferation, cytokine production, and encephalitogenic potential of PLP-reactive T cells. Specific induction of Notch1 and Notch3 transcripts were noted in PLP-reactive T cells upon Ag stimulation. However, using γ-secretase inhibitor and Abs blocking distinct Notch receptors, we have found that selective inhibition of Notch3, but not Notch1, receptor abrogated proliferation, Th1- and Th17-type responses of PLP-reactive T cells. Moreover, Notch3 inhibition in T cells correlated with the down-regulated expression of protein kinase Cθ, a kinase with important regulatory function within mature T cells. Thus, selective inhibition of the Notch3 receptor may have important effects on peripheral T cell responses and may offer a new attractive target in treating autoimmune diseases, including multiple sclerosis.

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Section: Discussionmentioning

confidence: 99%

Notch3 Inhibition in Myelin-Reactive T Cells Down-Regulates Protein Kinase Cθ and Attenuates Experimental Autoimmune Encephalomyelitis

Juryńczyk

Jurewicz

Raine

et al. 2008

The Journal of Immunology

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“…Expression of T-bet is induced by signaling through TCR, IFN-␥/STAT-1, and possibly Notch (4,23). We reasoned that TLR-activated DCs could be suppressing Th2 cell development by inducing T-bet.…”

Section: Neither Up-regulation Of T-bet Expression Nor Early Suppressmentioning

confidence: 99%

Suppression of Early IL-4 Production Underlies the Failure of CD4 T Cells Activated by TLR-Stimulated Dendritic Cells to Differentiate into Th2 Cells

Sun

Pearce

2007

The Journal of Immunology

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Dendritic cells (DCs) activated through TLRs provide a potent negative signal for Th2 cell development that is independent of positive signals for Th1 cell development such as IL-12 and IFN-γ. In this study we demonstrate that the ability of TLR-activated DCs to suppress Th2 cell development is Ag dose-independent and unique to DCs that have been activated through TLRs vs by cytokines. We show that TLR-activated DCs inhibit early IL-4 production by CD4 T cells and thus inhibit their ability to subsequently increase GATA-3 expression and commit to the Th2 lineage. This occurs independently of expression of the GATA-3 antagonist T-bet. Although CD4 T cells activated by TLR-activated DCs make IL-2, they are not capable of phosphorylating STAT5 in response to this cytokine. This inhibition of responsiveness to IL-2 appears to underlie the failure to make early IL-4. Our findings suggest that DCs provide instructional signals for T cell differentiation before cytokine-mediated Th cell selection and outgrowth.

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“…The anti-inflammatory cytokine TGF-b 1 has previously been shown to down-regulate T-bet [14,15,20], and in some but not all instances this is mediated by SMAD proteins [21]. Minter et al [22] recently reported that murine T-bet could be regulated by the transcriptional activator Notch1 via complexes formed on its promoter. Nonetheless, neither cis nor trans regulatory elements have been clearly defined for T-BET in humans.…”

Section: Introductionmentioning

confidence: 99%

Transcriptional control of human T‐BET expression: The role of Sp1

Min

Boyd

et al. 2007

Eur J Immunol

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Murine T-bet (T-box expressed in T cells) is a master regulator of IFN-c gene expressionin NK and T cells. T-bet also plays a critical role in autoimmunity, asthma and other diseases. However, cis elements or trans factors responsible for regulating T-bet expression remain largely unknown. Here, we report on our discovery of six Sp1-binding sites within the proximal human T-BET promoter that are highly conserved among mammalian species. Electrophoretic mobility shift assays demonstrate a physical association between Sp1 and the proximal T-BET promoter with a direct dose response between Sp1 expression and T-BET promoter activity. Ectopic overexpression of Sp1 also enhanced T-BET expression and cytokine-induced IFN-c secretion in NK cells and T cells. Mithramycin A, which blocks the binding of Sp1 to the T-BET promoter, diminished both T-BET expression and IFN-c protein production in monokine-stimulated primary human NK cells. Collectively, our results suggest that Sp1 is a positive transcriptional regulator of T-BET. As T-BET and IFN-c are critically important in inflammation, infection, and cancer, targeting Sp1, possibly with mithramycin A, may be useful for preventing and/ or treating diseases associated with aberrant T-BET or IFN-c expression.

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The nervous system and innate immunity: the neuropeptide connection

Cited by 431 publications

References 104 publications

Notch3 Inhibition in Myelin-Reactive T Cells Down-Regulates Protein Kinase Cθ and Attenuates Experimental Autoimmune Encephalomyelitis

Notch3 Inhibition in Myelin-Reactive T Cells Down-Regulates Protein Kinase Cθ and Attenuates Experimental Autoimmune Encephalomyelitis

Suppression of Early IL-4 Production Underlies the Failure of CD4 T Cells Activated by TLR-Stimulated Dendritic Cells to Differentiate into Th2 Cells

Transcriptional control of human T‐BET expression: The role of Sp1

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