Toll-like receptor–mediated regulation of zinc homeostasis influences dendritic cell function

Kitamura, Hiroyuki; Morikawa, Hideyuki; Kamon, Hokuto; Iguchi, Megumi; Hojyo, Shintaro; Fukada, Toshiyuki; Yamashita, Susumu; Kaisho, Tsuneyasu; Akira, Shizuo; Murakami, Masaaki; Hirano, Toshio

doi:10.1038/ni1373

Cited by 320 publications

(323 citation statements)

References 38 publications

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“…In dendritic cells, zinc movement caused by down-regulation of zinc importer Zip6 and up-regulation of zinc exporter ZnT-1 was involved in the maturation of dendritic cells (Kitamura et al 2006). Zinc movement regulated by the expression of zinc transporter may have crucial roles in performing the biological function of various cells.…”

Section: Discussionmentioning

confidence: 99%

Restraint stress up-regulates expression of zinc transporter Zip14 mRNA in mouse liver

et al. 2008

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The zinc concentration in the liver was significantly higher in mice at 12 h after the onset of restraint stress than that without stress. The IL-6 protein level in the serum was transiently elevated at 3 h after the onset of restraint stress, and the IL-6-responsive zinc transporter Zip14 mRNA in the liver was expressed markedly at 6 h. These results suggest that Zip14 plays a major role in the mechanism responsible for accumulation of zinc in the liver under restraint stress.

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Section: Discussionmentioning

confidence: 99%

Restraint stress up-regulates expression of zinc transporter Zip14 mRNA in mouse liver

et al. 2008

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“…Other genes preferentially induced by TREM-1 activation were the metallothionein family members MT1K, MT1E, and MT1F, which are cysteine-rich heavy metal-binding proteins implicated in binding, thereby reducing intracellular levels of available zinc (70). This may be of functional importance, because high intracellular zinc can suppress TNF and IL-1␤ production by monocytes (71) and inhibit LPSinduced expression of MHC class II and costimulatory molecules (72). All of these possibilities are currently speculative, yet they point to potentially significant cellular events that would be difficult to uncover in the absence of global gene expression profiling.…”

Section: Discussionmentioning

confidence: 99%

Innate Immune Responses to TREM-1 Activation: Overlap, Divergence, and Positive and Negative Cross-Talk with Bacterial Lipopolysaccharide

Dower

Ellis²,

Saraf³

et al. 2008

The Journal of Immunology

159

155

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TREM-1 (triggering receptor expressed on myeloid cells-1) is an orphan immunoreceptor expressed on monocytes, macrophages, and neutrophils. TREM-1 associates with and signals via the adapter protein DAP12/TYROBP, which contains an ITAM. TREM-1 activation by receptor cross-linking has been shown to be proinflammatory and to amplify some cellular responses to TLR ligands such as bacterial LPS. To investigate the cellular consequences of TREM-1 activation, we have characterized global gene expression changes in human monocytes in response to TREM-1 cross-linking in comparison to and combined with LPS. Both TREM-1 activation and LPS up-regulate chemokines, cytokines, matrix metalloproteases, and PTGS/COX2, consistent with a core inflammatory response. However, other immunomodulatory factors are selectively induced, including SPP1 and CSF1 (i.e., M-CSF) by TREM-1 activation and IL-23 and CSF3 (i.e., G-CSF) by LPS. Additionally, cross-talk between TREM-1 activation and LPS occurs on multiple levels. Although synergy in GM-CSF protein production is reflected in commensurate mRNA abundance, comparable synergy in IL-1β protein production is not. TREM-1 activation also attenuates the induction of some LPS target genes, including those that encode IL-12 cytokine family subunits. Where tested, positive TREM-1 outputs are greatly reduced by the PI3K inhibitor wortmannin, whereas this attenuation is largely PI3K independent. These experiments provide a detailed analysis of the cellular consequences of TREM-1 activation and highlight the complexity in signal integration between ITAM- and TLR-mediated signaling.

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“…The functional significance of these observations remains to be directly tested and elucidated. However, given the importance of zinc homeostasis for T cell function (47)(48)(49)(50)(51)(52)(53), coupled with our observations suggesting large scale downregulation of T cell-related genes, the overall data provide the basis for biologically plausible and testable hypotheses surrounding zinc homeostasis and lymphocyte dysfunction in pediatric septic shock.…”

Section: R E S E a R C H A R T I C L E M O L M Ementioning

confidence: 99%

Genome-Level Longitudinal Expression of Signaling Pathways and Gene Networks in Pediatric Septic Shock

Shanley

Cvijanovich²,

Lin

et al. 2007

Mol Med

112

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We have conducted longitudinal studies focused on the expression profiles of signaling pathways and gene networks in children with septic shock. Genome-level expression profiles were generated from whole blood-derived RNA of children with septic shock (n = 30) corresponding to day one and day three of septic shock, respectively. Based on sequential statistical and expression filters, day one and day three of septic shock were characterized by differential regulation of 2,142 and 2,504 gene probes, respectively, relative to controls (n = 15). Venn analysis demonstrated 239 unique genes in the day one dataset, 598 unique genes in the day three dataset, and 1,906 genes common to both datasets. Functional analyses demonstrated timedependent, differential regulation of genes involved in multiple signaling pathways and gene networks primarily related to immunity and inflammation. Notably, multiple and distinct gene networks involving T cell-and MHC antigen-related biology were persistently downregulated on both day one and day three. Further analyses demonstrated large scale, persistent downregulation of genes corresponding to functional annotations related to zinc homeostasis. These data represent the largest reported cohort of patients with septic shock subjected to longitudinal genome-level expression profiling. The data further advance our genome-level understanding of pediatric septic shock and support novel hypotheses.

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Toll-like receptor–mediated regulation of zinc homeostasis influences dendritic cell function

Cited by 320 publications

References 38 publications

Restraint stress up-regulates expression of zinc transporter Zip14 mRNA in mouse liver

Restraint stress up-regulates expression of zinc transporter Zip14 mRNA in mouse liver

Innate Immune Responses to TREM-1 Activation: Overlap, Divergence, and Positive and Negative Cross-Talk with Bacterial Lipopolysaccharide

Genome-Level Longitudinal Expression of Signaling Pathways and Gene Networks in Pediatric Septic Shock

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