Mature Dendritic Cells Respond to SDF-1, but not to Several β-Chemokines

Delgado, Elena; Finkel, Victoria; Baggiolini, Marco; Mackay, Charles R.; Steinman, Ralph M.; Granelli‐Piperno, Angela

doi:10.1016/s0171-2985(98)80073-9

Cited by 83 publications

(60 citation statements)

References 32 publications

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“…At variance with iDC differentiated from CD34 ϩ HPC, which express CCR5 but lack CXCR4, we found that immature MDDC coexpress CCR5 and CXCR4 (33,61,62). In line with these findings, both R5 HIV-1 Ba-L and X4 HIV-1 LAI efficiently entered these iDC, although virus production was ϳ50-fold higher in HIV-1 Ba-L -than in HIV-1 LAI -infected cultures in a short-term assay.…”

Section: Discussionmentioning

confidence: 78%

The Maturation of Dendritic Cells Results in Postintegration Inhibition of HIV-1 Replication

Bakri

Schiffer

Zennou

et al. 2001

The Journal of Immunology

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Maturation of dendritic cells (DC) is known to result in decreased capacity to produce HIV due to postentry block of its replicative cycle. In this study, we compared the early phases of this cycle in immature DC (iDC) and mature DC (mDC) generated from monocytes cultured with GM-CSF and IL-4, trimeric CD40 ligand (DCCD40LT), or monocyte-conditioned medium (DCMCM) being added or not from day 5. Culture day 8 cells exposed to X4 HIV-1LAI or R5 HIV-1Ba-L were analyzed by semiquantitative R-U5 PCR, which detects total HIV DNA. CXC chemokine receptor 4low (CXCR4low) CCR5+ iDC harbored similar viral DNA amounts when exposed to either strain. HIV-1LAI entered more efficiently into DCCD40LT or DCMCM with up-regulated CXCR4. CCR5low DCCD40LT still allowed entry of HIV-1Ba-L, whereas CCR5− DCMCM displayed reduced permissivity to this virus. Comparing amounts of late (long terminal repeat (LTR)-gag PCR) and total (R-U5 PCR) viral DNA products showed that HIV-1Ba-L reverse transcription was more efficient than that of HIV-1LAI, but was not affected by DC maturation. Southern blot detection of linear, circular, and integrated HIV DNA showed that maturation affected neither HIV-1 nuclear import nor integration. When assessing virus transcription by exposing iDC to pNL4-3.GFP or pNL4-3.Luc viruses pseudotyped with the G protein of vesicular stomatitis virus (VSV-G), followed by culture with or without CD40LT or MCM, GFP and luciferase activities decreased by 60–75% in mDC vs iDC. Thus, reduced HIV replication in mDC is primarily due to a postintegration block occurring mainly at the transcriptional level. We could not relate this block to altered expression and nuclear localization of NF-κB proteins and SP1 and SP3 transcription factors.

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Section: Discussionmentioning

confidence: 78%

The Maturation of Dendritic Cells Results in Postintegration Inhibition of HIV-1 Replication

Bakri

Schiffer

Zennou

et al. 2001

The Journal of Immunology

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“…It is theoretically possible that the changes in responsiveness to certain chemokines could even be due to chemokine production by DC themselves. Clearly, detailed studies of chemokine and receptor gene polymorphisms and mRNA expression will be required for further insights into these phenomena; changes in receptor mRNA expression during maturation of monocyte-derived DC, including decreased CCR5 and/or increased CXCR4 mRNA levels, have already been observed by other investigators ( [36], and A. Lanzavecchia, personal communication). It is interesting that inhibition of chemokine receptor expression by LPS was first described in monocytes [37,38], cells that were used to generate the DC used in this study.…”

Section: Discussionmentioning

confidence: 80%

Dendritic cell chemotaxis and transendothelial migration are induced by distinct chemokines and are regulated on maturation

et al. 1998

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The capacity of dendritic cells (DC) to initiate immune responses is dependent on their specialized migratory and tissue homing properties. Chemotaxis and transendothelial migration (TEM) of DC were studied in vitro. Immature DC were generated by culture of human monocytes in granulocyte-macrophage colony-stimulating factor and IL-4. These cells exhibited potent chemotaxis and TEM responses to the CC chemokines macrophage inflammatory protein (MIP)-1 § , MIP-1 g , RANTES, and monocyte chemotactic protein-3, and weak responses to the CC chemokine MIP-3 g and the CXC chemokine stromal cell-derived factor (SDF)-1 § . Maturation of DC induced by culture in lipopolysaccharide, TNF- § or IL-1 g reduced or abolished responses to the former CC chemokines but markedly enhanced responses to MIP-3 g and SDF-1 § . This correlated with changes in chemokine receptor expression: CCR5 expression was reduced while CXCR4 expression was enhanced. These findings suggest two stages for regulation of DC migration in which one set of chemokines may regulate recruitment into or within tissues, and another egress from the tissues.

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“…(70)(71)(72) An increase in free cytosolic Ca 2þ is also essential for the uptake and processing of apoptotic bodies. (73) Chemotactic molecules and Tcell-derived signals uniformly produce Ca 2þ increases in DCs, (74)(75)(76)(77)(78) suggesting that Ca 2þ transients regulate DC maturation and their capacity to initiate adaptive immune responses.…”

Section: Dendritic Cell (Dc) Functionmentioning

confidence: 99%

The IRBIT domain adds new functions to the AHCY family

2008

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SummaryDuring the past few years, the IRBIT domain has emerged as an important add-on of S-adenosyl-L-homocystein hydrolase (AHCY), thereby creating the new family of AHCY-like proteins. In this review, we discuss the currently available data on this new family of proteins. We describe the IRBIT domain as a unique part of these proteins and give an overview of its regulation via (de)phosphorylation and proteolysis. The second part of this review is focused on the potential functions of the AHCY-like proteins. We propose that the IRBIT domain serves as an anchor for targeting AHCY-like proteins towards cytoplasmic targets. This leads to regulation of (i) The AHCY family AHCY S-adenosyl-L-homocystein (SAH) hydrolase (AHCY) is a ubiquitous, tetrameric enzyme that catalyzes the reversible hydrolysis of SAH to adenosine and L-homocysteine. SAH is formed as a by-product of S-adenosyl-L-methionine (SAM) through transmethylation reactions. The hydrolysis of SAH is required to maintain low cellular concentrations of SAH, which is a product inhibitor of S-adenosyl-L-methionine (SAM)-dependent transmethylation reactions.(1-4) Inhibition of AHCY results in the intracellular accumulation of SAH, causing a significant increase in the intracellular SAH/SAM ratio and the subsequent inhibition of SAM-dependent methylations.( 5 -8) SAM is the major methyl donor for delivery of methyl groups to DNA, RNA, proteins and cellular metabolites in eukaryotes and SAH hydrolysis is the only source of homocysteine in mammals.(9) AHCY has become an attractive target for design of broad-spectrum antiviral agents because of the inhibitory effects of elevated intracellular SAH concentrations on viral mRNA cap-methylating enzymes. (10,11) In addition to these antiviral effects, AHCY inhibitors have also been attributed antiparasitic, (12,13) anti-arthritic (14) and immunosuppressive (15) effects.The importance of AHCY for mammalian survival is suggested by the fact that a chromosomal deletion that includes the gene encoding AHCY causes embryonic lethality in mice.(16) Elevated homocysteine levels have been reported as a risk factor for dementia and Alzheimer's disease, (17) and as a possible risk marker for vascular disease. (18,19) Human AHCY deficiency, such as in hypermethionemia, results in severe biochemical abnormalities, including plasma elevations of 150-fold in SAH, 30-fold in SAM and 12-fold in methionine. (20,21) So far, three mutations in the AHCY gene have been found to reduce the activity of the AHCY enzyme, resulting in the signs and symptoms of hypermethionemia. (22,23) AHCY orthologues have been identified in many species, including bacteria, nematodes, yeast, plants, insects and vertebrates. In contrast, the AHCY-like (AHCYL) family members AHCYL1 (also termed IRBIT, the inositol 1,4, 5-trisphosphate (IP 3 ) receptor (IP 3 R) binding protein released by IP 3 ) and AHCYL2 (KIAA0828 in human) are only predicted in segmented multicellular organisms, like vertebrates (eg Takifugu rubripes (fugu fish), Danio rerio (zebrafish), Xen...

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Mature Dendritic Cells Respond to SDF-1, but not to Several β-Chemokines

Cited by 83 publications

References 32 publications

The Maturation of Dendritic Cells Results in Postintegration Inhibition of HIV-1 Replication

The Maturation of Dendritic Cells Results in Postintegration Inhibition of HIV-1 Replication

Dendritic cell chemotaxis and transendothelial migration are induced by distinct chemokines and are regulated on maturation

The IRBIT domain adds new functions to the AHCY family

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