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Biomedical subjects

Christopher K Glass

Publications and source records attributed to Christopher K Glass.

49 records · Page 3Linked to original sources
PubMed2002

WY14,643, a PPAR alpha ligand, has profound effects on immune responses in vivo.

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors with diverse actions. PPARalpha and PPARgamma are expressed in different lymphocyte subpopulations. Recently, we have observed that PPARalpha ligands elicit augmented IL-4 expression in cultures of mitogen-activated splenocytes. The following studies were undertaken to characterize the in vivo effects of WY14,643, a PPARalpha ligand. Our studies demonstrate that oral administration of WY14,643 markedly reduces splenocyte number in immunized and nonimmunized C57BL/6 mice. Mice fed WY14,643 display impaired IgG responses to myelin oligodendrocyte glycoprotein peptide 35-55 (pMOG(35-55)), following immunization with pMOG(35-55)/CFA. Following in vitro restimulation with pMOG(35-55), splenocytes harvested from WY14,643-fed mice demonstrate impaired production of IFN-gamma, IL-6, and TNF-alpha despite similar proliferative responses. We also demonstrate higher expression of PPARalpha in B than T cells. Finally, to obtain an understanding of the cause of splenocyte depletion with fibrate therapy, we studied the effect of WY14,643 on apoptosis of activated splenocytes. WY14,643 in vitro induces apoptosis in lymphocytes and this effect appears to occur in a PPARalpha-independent manner. Thus WY14,643, a fibrate, is a profound immunosuppressive agent.

Administration, Oral↗
PubMed2002

Identification of a Wnt/Dvl/beta-Catenin --> Pitx2 pathway mediating cell-type-specific proliferation during development.

Understanding the cell type-specific molecular mechanisms by which distinct signaling pathways combinatorially control proliferation during organogenesis is a central issue in development and disease. Here, we report that the bicoid-related transcription factor Pitx2 is rapidly induced by the Wnt/Dvl/beta-catenin pathway and is required for effective cell-type-specific proliferation by directly activating specific growth-regulating genes. Regulated exchange of HDAC1/beta-catenin converts Pitx2 from repressor to activator, analogous to control of TCF/LEF1. Pitx2 then serves as a competence factor required for the temporally ordered and growth factor-dependent recruitment of a series of specific coactivator complexes that prove necessary for Cyclin D2 gene induction. The molecular strategy underlying interactions between the Wnt and growth factor-dependent signaling pathways in cardiac outflow tract and pituitary proliferation is likely to be prototypic of cell-specific proliferation strategies in other tissues.

Adaptor Proteins, Signal Transducing↗
PubMed2002

TH2 cytokines and allergic challenge induce Ym1 expression in macrophages by a STAT6-dependent mechanism.

The diverse functions of macrophages as participants in innate and acquired immune responses are regulated by the specific milieu of environmental factors, cytokines, and other signaling molecules that are encountered at sites of inflammation. Microarray analysis of the transcriptional response of mouse peritoneal macrophages to the T(H)2 cytokine interleukin-4 (IL-4) identified Ym1 and arginase as the most highly up-regulated genes, exhibiting more than 68- and 88-fold induction, respectively. Molecular characterization of the Ym1 promoter in transfected epithelial and macrophage cell lines revealed the presence of multiple signal transducers and activators of transcription 6 (STAT6) response elements that function in a combinatorial manner to mediate transcriptional responses to IL-4. The participation of STAT6 as an obligate component of protein complexes binding to these sites was established by analysis of nuclear extracts derived from STAT6-deficient macrophages. Macrophage expression of Ym1 was highly induced in vivo by an IL-4- and STAT6-dependent mechanism during the evolution of allergic peritonitis, supporting the biological relevance of the IL-4-dependent pathway characterized ex vivo in peritoneal macrophages. These studies establish Ym1 as a highly inducible STAT6-dependent transcript in T(H)2-biased inflammation and define Cis-active elements in the Ym1 promoter that are required for this transcriptional response.

Animals↗
PubMed2002

Exchange of N-CoR corepressor and Tip60 coactivator complexes links gene expression by NF-kappaB and beta-amyloid precursor protein.

Defining the molecular mechanisms that integrate diverse signaling pathways at the level of gene transcription remains a central issue in biology. Here, we demonstrate that interleukin-1beta (IL-1beta) causes nuclear export of a specific N-CoR corepressor complex, resulting in derepression of a specific subset of NF-kappaB-regulated genes, exemplified by the tetraspanin KAI1 that regulates membrane receptor function. Nuclear export of the N-CoR/TAB2/HDAC3 complex by IL-1beta is temporally linked to selective recruitment of a Tip60 coactivator complex. Surprisingly, KAI1 is also directly activated by a ternary complex, dependent on the acetyltransferase activity of Tip60, consisting of the presenilin-dependent C-terminal cleavage product of the amyloid beta precursor protein (APP), Fe65, and Tip60, identifying a specific in vivo gene target of an APP-dependent transcription complex in the brain.

Acetyltransferases↗
PubMed2002

An induced Ets repressor complex regulates growth arrest during terminal macrophage differentiation.

Defining the molecular mechanisms that coordinately regulate proliferation and differentiation is a central issue in development. Here, we describe a mechanism in which induction of the Ets repressor METS/PE1 links terminal differentiation to cell cycle arrest. Using macrophages as a model, we provide evidence that METS/PE1 blocks Ras-dependent proliferation without inhibiting Ras-dependent expression of cell type-specific genes by selectively replacing Ets activators on the promoters of cell cycle control genes. Antiproliferative effects of METS require its interaction with DP103, a DEAD box-containing protein that assembles a novel corepressor complex. Functional interactions between the METS/DP103 complex and E2F/ pRB family proteins are also necessary for inhibition of cellular proliferation, suggesting a combinatorial code that directs permanent cell cycle exit during terminal differentiation.

Animals↗
PubMed2002

Maternal hypercholesterolemia during pregnancy promotes early atherogenesis in LDL receptor-deficient mice and alters aortic gene expression determined by microarray.

BACKGROUND: Maternal hypercholesterolemia during pregnancy is associated with markedly enhanced fatty streak formation in human fetal aortas and accelerated progression of atherosclerosis in normocholesterolemic children. METHODS AND RESULTS: To establish the causal role of maternal hypercholesterolemia in a genetically homogeneous murine model and to test the hypothesis that pathogenic events during fetal development result in persistent changes in arterial gene expression, female LDL receptor-deficient (LDLR(-/-)) mice were fed regular chow or high-fat diets supplemented with 0.075% or 1.25% cholesterol during pregnancy. Lesion sizes were determined in the aortic origin of their chow-fed offspring at 3 months. Maternal hypercholesterolemia more than doubled lesion sizes in male offspring (P<0.0001 for the 0.0075% cholesterol group). Microarray analysis of the expression of 11 000 murine genes in the nonatherosclerotic descending aorta by Affymetrix gene chips suggested that 139 genes were significantly regulated in offspring of hypercholesterolemic mothers. A subset of 12 of the upregulated transcripts was subjected to secondary analysis by semiquantitative PCR of pooled RNA and 4 genes were found to be upregulated >1.7-fold. Quantitative PCR for one of these genes using RNA from individual mice yielded similar results. Comparative immunostaining for several of the above genes also indicated increased protein content in offspring of hypercholesterolemic mothers. CONCLUSIONS: These findings establish an atherogenic effect of maternal hypercholesterolemia in genetically uniform mice and indicate that changes in aortic gene expression persist long after fetal exposure to hypercholesterolemia. In addition to elucidating pathogenic mechanisms initiated during fetal development, this approach may identify genes in morphologically normal arteries that influence the susceptibility to classical risk factors of atherosclerosis.

Animals↗
PubMed2002

Regulation of cytokine expression by ligands of peroxisome proliferator activated receptors.

Peroxisome proliferator activated receptors (PPARs) are ligand-activated transcription factors with diverse actions including adipocyte differentiation and lipid metabolism. Recent studies have revealed anti-inflammatory activities, but the majority of these studies have been performed in monocyte/macrophages. In these studies, we investigate the effects of PPAR ligands in murine mitogen-activated splenocytes. Ciglitazone, a PPARgamma ligand, consistently decreased IFN-gamma and IL-2 production by mitogen-activated splenocytes and had modest effects on splenocyte proliferation. The effects of WY14,643, a representative of the fibrate class of PPARalpha ligands, on splenocyte proliferation and IL-2 levels are less marked than those observed with the PPARgamma ligand. In addition, treatment with WY14,643 and other fibrates led to marked increases in supernatant concentrations of IL-4. However, treatment with a potent and specific PPARalpha ligand (GW7,647) did not augment IL-4. Also, WY14,643 induced IL-4 expression in splenocytes from PPARalpha knockout mice, suggesting that the fibrate effect on IL-4 was largely through a PPARalpha-independent mechanism. This increase in IL-4 was associated with and causatively related to augmented expression of CD23 by CD45R/B220(+) cells. We also demonstrate that PPARgamma gene expression is up-regulated in T cells by mitogen activation, that it is positively regulated by IL-4 and WY14,643, and that it is blocked by anti-IL-4. Finally, we demonstrate that WY14,643 can modestly augment IL-4 promoter activity in a PPARalpha-independent manner. In concert, these findings support the roles of PPAR ligands in modulating inflammatory responses involving lymphocytes but also establish potent effects of the fibrate class of PPARalpha ligands on IL-4 expression that are receptor independent.

Adjuvants, Immunologic↗
PubMed2002

Nuclear receptor coregulators: multiple modes of modification.

Many proteins have been characterized as coregulators that can be recruited by DNA-binding nuclear receptors to influence transcriptional regulation. Recent genetic and biochemical studies have shown that cellular levels of coregulators are crucial for nuclear receptor-mediated transcription, and many coregulators have been shown to be targets for diverse intracellular signaling pathways and post-translational modifications. This review focuses on the different modes of regulation of nuclear receptor coregulators and the implications for tissue- and context-specific transcriptional responses to hormone and membrane receptor signaling.

Animals↗
PubMed2002

The role of transcription factors in allergic inflammation.

The induction of allergic inflammation and the expression of allergic disorders are dependent on the coordinated regulation of numerous genes. The products of these genes determine lymphocyte phenotype, immunologic responsiveness, eosinophil and mast cell development, activation, migration and life span, adhesion molecule expression, cytokine synthesis, cell-surface receptor display, and processes governing fibrosis and tissue repair. Although the expression of gene products involved in these processes is regulated at multiple levels (eg, transcription, mRNA processing, translation, phosphorylation, and degradation), transcription represents an essential and often the most important determinant of their contribution to cellular function. Signal-dependent and cell type-specific regulation of gene expression is generally achieved by means of combinatorial interactions between sequence-specific transcription factors that recruit chromatin remodeling machinery and general transcription factors to promoter and enhancer regions of RNA polymerase II-dependent genes. As targets of signal-transduction pathways, transcription factors integrate the response of the cell to the myriad of inputs it receives. This integration can be accomplished by the effect of signaling cascades on the activation status or subcellular locus of transcription factors or by transcription factor dimerization induced by means of ligand binding. This review will identify the major families of transcription factors important in allergic mechanisms and discuss their interactions, their mechanisms of action, and their interrelated and competitive actions, as well as implications for therapy of allergic disorders.

Animals↗
PubMed2002

Roles of peroxisome proliferator-activated receptor gamma in lipid homeostasis and inflammatory responses of macrophages.

Monocytes play a critical role in atherogenesis by their inflammatory signals and differentiation into macrophage foam cells through cholesterol accumulation. The seminal finding of high levels of the peroxisome proliferator-activated receptor gamma in macrophage foam cells has opened up the prospect that its ligands, most importantly the thiazolidinedione class of drugs, might directly influence the development of atheromatous lesions. The present review weighs the growing evidence on regulation of both inflammatory responses and cholesterol homeostasis in macrophages by peroxisome proliferator-activated receptor gamma ligands with regard to their overall impact as antiatherogenic agents.

ATP-Binding Cassette Transporters↗
PubMed2002

Conditional disruption of the peroxisome proliferator-activated receptor gamma gene in mice results in lowered expression of ABCA1, ABCG1, and apoE in macrophages and reduced cholesterol efflux.

Disruption of the peroxisome proliferator-activated receptor gamma (PPAR gamma) gene causes embryonic lethality due to placental dysfunction. To circumvent this, a PPAR gamma conditional gene knockout mouse was produced by using the Cre-loxP system. The targeted allele, containing loxP sites flanking exon 2 of the PPAR gamma gene, was crossed into a transgenic mouse line expressing Cre recombinase under the control of the alpha/beta interferon-inducible (MX) promoter. Induction of the MX promoter by pIpC resulted in nearly complete deletion of the targeted exon, a corresponding loss of full-length PPAR gamma mRNA transcript and protein, and marked reductions in basal and troglitazone-stimulated expression of the genes encoding lipoprotein lipase, CD36, LXR alpha, and ABCG1 in thioglycolate-elicited peritoneal macrophages. Reductions in the basal levels of apolipoprotein E (apoE) mRNA in macrophages and apoE protein in total plasma and high-density lipoprotein (HDL) were also observed in pIpC-treated PPAR gamma-MXCre(+) mice. Basal cholesterol efflux from cholesterol-loaded macrophages to HDL was significantly reduced after disruption of the PPAR gamma gene. Troglitazone selectively inhibited ABCA1 expression (while rosiglitazone, ciglitazone, and pioglitazone had little effect) and cholesterol efflux in both PPAR gamma-deficient and control macrophages, indicating that this drug can exert paradoxical effects on cholesterol homeostasis that are independent of PPAR gamma. Together, these data indicate that PPAR gamma plays a critical role in the regulation of cholesterol homeostasis by controlling the expression of a network of genes that mediate cholesterol efflux from cells and its transport in plasma.

ATP Binding Cassette Transporter 1↗