Macrophage PPAR gamma Co-activator-1 alpha participates in repressing foam cell formation and atherosclerosis in response to conjugated linoleic acid.

Conjugated linoleic acid (CLA) has the unique property of inducing regression of pre-established murine atherosclerosis. Understanding the mechanism(s) involved may help identify endogenous pathways that reverse human atherosclerosis. Here, we provide evidence that CLA inhibits foam cell formation via regulation of the nuclear receptor coactivator, peroxisome proliferator-activated receptor (PPAR)-γ coactivator (PGC)-1α, and that macrophage PGC-1α plays a role in atheroprotection in vivo.

Mechanisms establishing TLR4-responsive activation states of inflammatory response genes.

Precise control of the innate immune response is required for resistance to microbial infections and maintenance of normal tissue homeostasis. Because this response involves coordinate regulation of hundreds of genes, it provides a powerful biological system to elucidate the molecular strategies that underlie signal- and time-dependent transitions of gene expression. Comprehensive genome-wide analysis of the epigenetic and transcription status of the TLR4-induced transcriptional program in macrophages suggests that Toll-like receptor 4 (TLR4)-dependent activation of nearly all immediate/early- (I/E) and late-response genes results from a sequential process in which signal-independent factors initially establish basal levels of gene expression that are then amplified by signal-dependent transcription factors.

Pomalidomide and lenalidomide induce p21 WAF-1 expression in both lymphoma and multiple myeloma through a LSD1-mediated epigenetic mechanism.

Lenalidomide and pomalidomide have both been evaluated clinically for their properties as anticancer agents, with lenalidomide being available commercially. We previously reported that both compounds cause cell cycle arrest in Burkitt's lymphoma and multiple myeloma cell lines by increasing the level of p21(WAF-1) expression. In the present study, we unravel the molecular mechanism responsible for p21(WAF-1) up-regulation using Namalwa cells as a human lymphoma model.

Differential repression of c-myc and cdc2 gene expression by ERF and PE-1/METS.

The molecular mechanisms that control the proliferation and differentiation of specific cell types remain poorly understood. Positive ETS factors play important roles in mediating proliferative responses to Ras/MAPK signaling in many cell types following mitogenic stimulation. PE-1/METS, a member of the ETS-domain family transcription factors that functions as a transcriptional repressor, can block mitogenic responses mediated by positively acting Ets factors.

n-3 and n-6 polyunsaturated fatty acids induce the expression of COX-2 via PPARgamma activation in human keratinocyte HaCaT cells.

Polyunsaturated fatty acids (PUFA) n-3 inhibit inflammation, in vivo and in vitro in keratinocytes. We examined in HaCaT keratinocyte cell line whether eicosapentaenoic acid (EPA) a n-3 PUFA, gamma-linoleic acid (GLA) a n-6 PUFA, and arachidic acid a saturated fatty acid, modulate expression of cyclooxygenase-2 (COX-2), an enzyme pivotal to skin inflammation and reparation. We demonstrate that only treatment of HaCaT with GLA and EPA or a PPARgamma ligand (roziglitazone), induced COX-2 expression (protein and mRNA).

Histone methylation-dependent mechanisms impose ligand dependency for gene activation by nuclear receptors.

Nuclear receptors undergo ligand-dependent conformational changes that are required for corepressor-coactivator exchange, but whether there is an actual requirement for specific epigenetic landmarks to impose ligand dependency for gene activation remains unknown. Here we report an unexpected and general strategy that is based on the requirement for specific cohorts of inhibitory histone methyltransferases (HMTs) to impose gene-specific gatekeeper functions that prevent unliganded nuclear receptors and other classes of regulated transcription factors from binding to their target gene promoters and causing constitutive gene activation in the absence of stimulating signals. This strategy, based at least in part on an HMT-dependent inhibitory histone code, imposes a requirement for specific histone demethylases, including LSD1, to permit ligand- and signal-dependent activation of regulated gene expression.

Mnt-deficient mammary glands exhibit impaired involution and tumors with characteristics of myc overexpression.

The proto-oncogene c-Myc plays a central role in cell growth and the development of human tumors. c-Myc interacts with Max and Myc-Max complexes bind to E-box and related sequences to activate transcription. Max also interacts with Mnt but Mnt-Max complexes repress transcription when bound to these sequences.

PE-1/METS, an antiproliferative Ets repressor factor, is induced by CREB-1/CREM-1 during macrophage differentiation.

The molecular mechanisms involved in regulating the balance between cellular proliferation and differentiation remain poorly understood. Members of the Ets-domain family of transcription factors are candidates for proteins that might differentially regulate cell cycle control and cell type-specific genes during the differentiation of myeloid progenitor cells. The Ets repressor PE-1/METS has been suggested to contribute to growth arrest during terminal macrophage differentiation by repressing Ets target genes involved in Ras-dependent proliferation.

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.

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.