The Plasticity of Dendritic Cell Responses to Pathogens and Their Components

Huang, Qian; Dongyu, Liu; Majewski, Paul; Schulte, Leah C.; Korn, Joshua M.; Young, Richard A.; Lander, Eric S.; Hacohen, Nir

doi:10.1126/science.294.5543.870

Cited by 691 publications

(569 citation statements)

References 30 publications

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“…In agreement with the human data (Perrier et al 18 and references therein; Huang et al 19 ), treatment with LPS had a profound effect on the transcriptional profile of the mouse DC. Additionally, the set of mouse genes modulated by LPS corresponds to those reported for human.…”

Section: Transcriptional Profile Of Lps-treated DCsupporting

confidence: 88%

TGFβ-dependent gene expression profile during maturation of dendritic cells

et al. 2007

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Primary immune response to pathogens involves the maturation of antigen-presenting dendritic cells (DC). Bacterial lipopolysacharride (LPS) is a potent inducer of DC maturation, whereas the transforming growth factor b (TGFb) attenuates much of this process. Here, we analyzed the global gene expression pattern in LPS-treated bone marrow derived DC during inhibition of their maturation process by TGFb. Exposure of DC to LPS induces a pronounced cell response, manifested in altered expression of a large number of genes. Interestingly, TGFb did not affect most of the LPS responding genes. Nevertheless, analysis identified a subset of genes that did respond to TGFb, among them the two inflammatory cytokines interleukin (IL)-12 and IL-18. Expression of IL-12, the major proinflammatory cytokine secreted by mature DC, was downregulated by TGFb, whereas the expression level of the proinflammatory cytokine IL-18, known to potentiate the IL-12 effect, was upregulated. Expression of the peroxisome proliferator-activated receptor g (PPARg) increased in response to TGFb, concomitantly with reduced expression of chemokine receptor 7 (CCR7). This finding supports the possibility that TGFbdependent inhibition of CCR7 expression in DC is mediated by PPARg.

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Section: Transcriptional Profile Of Lps-treated DCsupporting

confidence: 88%

TGFβ-dependent gene expression profile during maturation of dendritic cells

et al. 2007

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“…The quantitative effects of lipid A on reprogramming dendritic cell gene expression are consistent with other studies examining the impact of TLR agonists and pathogens on the macrophage or dendritic cell transcriptome [21][22][23][24]. Importantly, the expression of 47.4% (n=200) of all genes that are regulated by lipid A in wild-type dendritic cells (n=421) was significantly changed by G 2-fold in cells of Trif Lps2/Lps2 mutant mice.…”

Section: Trif Is a Major Regulator Of Tlr4-stimulated Dendritic Cell supporting

confidence: 85%

Identification of a TLR4‐ and TRIF‐dependent activation program of dendritic cells

et al. 2004

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Dendritic cell activation by Toll-like receptors (TLR) is crucial for the generation of protective immune responses. In addition to the common myeloid differentiation factor 88 (MyD88)-dependent signaling pathway, TLR4 engages the adaptor protein Toll/IL-1 receptor (TIR)-domain-containing adaptor inducing IFN-g (TRIF), leading to interferon regulatory factor 3 (IRF-3) activation and type I interferon production. Using microarray expression profiling we now identify TRIF as a major regulator of the TLR4-triggered activation program of dendritic cells. We show that the expression of 47% of the genes that are responsive to TLR4 stimulation in wild-type dendritic cells is significantly altered in cells carrying a loss-of-function mutation of TRIF. Specifically, expression of IL-12, IL-18, and IL-23 was impaired in the absence of functional TRIF, suggesting that TLR4-promoted Th1 responses are TRIFdependent. Furthermore, we provide evidence that TRIF regulates TLR4-mediated gene expression both by type I IFN-dependent and -independent mechanisms. Whereas dendritic cell production of CXCL10 and CCL12 was dependent on both TRIF and the type I interferon receptor, expression of IL-6 required TRIF but not type I interferon activity. Functional TRIF was also required for the normal induction of numerous genes considered important for host defense against diverse pathogens. Together, these data therefore identify TRIF as a crucial regulator of TLR4-dependent dendritic cell responses.

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“…Different TLR are reported to share a common signal transduction pathway similar to that of the interleukin-1 receptor [33]. However, it has been demonstrated that stimulation of TLR2, TLR3 or TLR4 induces separate sets of genes in some mammalian cell culture systems [34]. The latter finding is in agreement with the present study, demonstrating that a combined LPS and poly-I-C stimulation resulted in enhancement of bradykinin-induced contractions, much stronger than the ones obtained with each agonist separately.…”

Section: Discussionmentioning

confidence: 99%

Toll‐like receptor stimulation induces airway hyper‐responsiveness to bradykinin, an effect mediated by JNK and NF‐κB signaling pathways

et al. 2004

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Airway infections induce hyper-responsiveness in asthmatic patients. Toll-like receptors (TLR) mediate inflammatory responses to microbes. Occurrence and effects of TLR2, TLR3 and TLR4 were examined in a mouse organ culture model of asthma focusing on the smooth muscle responses to bradykinin. TLR2, TLR3 and TLR4 mRNA, and TLR2 and TLR4 immunoreactivity were detected in the tracheal muscle layer. Tracheal organ culture for 1 or 4 days with lipopolysaccharide (LPS; TLR2/4 agonist) or polyinosinic polycytidylic acid (poly-I-C; TLR3 agonist) enhanced bradykinin-and [des-Arg 9 ]-bradykinin-induced contractions. Simultaneous LPS and poly-I-C treatment resulted in synergistic enhancement of bradykinin-induced contraction. In carbachol-pre-contracted segments TLR stimulation induced less potent relaxations to bradykinin and [des-Arg 9 ]-bradykinin. The LPS and poly-I-C enhancement of bradykinin-induced contraction was inhibited by the transcriptional inhibitor actinomycin-D, dexamethasone, the proteasome inhibitor MG-132 and the c-Jun Nterminal kinase (JNK) inhibitor SP600125. LPS and poly-I-C induced translocation of NF-‹ B p65 to the nucleus and up-regulation of kinin B 1 and B 2 receptor mRNA. In summary, TLR2, TLR3 and TLR4 are expressed in the mouse tracheal smooth muscle. Costimulation of these receptors results in NF-‹ B-and JNK-mediated transcription of B 1 and B 2 receptor, inducing hyper-responsiveness to bradykinin.

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The Plasticity of Dendritic Cell Responses to Pathogens and Their Components

Cited by 691 publications

References 30 publications

TGFβ-dependent gene expression profile during maturation of dendritic cells

TGFβ-dependent gene expression profile during maturation of dendritic cells

Identification of a TLR4‐ and TRIF‐dependent activation program of dendritic cells

Toll‐like receptor stimulation induces airway hyper‐responsiveness to bradykinin, an effect mediated by JNK and NF‐κB signaling pathways

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