As an inhibitor of cyclin-dependent kinases, p16INK4A is an important tumour suppressor and inducer of cellular senescence that is often inactivated during the development of cancer by promoter DNA methylation. Using newly established lymphoblastoid cell lines (LCLs) expressing a conditional EBNA3C from recombinant EBV, we demonstrate that EBNA3C inactivation initiates chromatin remodelling that resets the epigenetic status of p16INK4A to permit transcriptional activation: the polycomb-associated repressive H3K27me3 histone modification is substantially reduced, while the activation-related mark H3K4me3 is modestly increased. Activation of EBNA3C reverses the distribution of these epigenetic marks, represses p16INK4A transcription and allows proliferation. LCLs lacking EBNA3A express relatively high levels of p16INK4A and have a similar pattern of histone modifications on p16INK4A as produced by the inactivation of EBNA3C. Since binding to the co-repressor of transcription CtBP has been linked to the oncogenic activity of EBNA3A and EBNA3C, we established LCLs with recombinant viruses encoding EBNA3A- and/or EBNA3C-mutants that no longer bind CtBP. These novel LCLs have revealed that the chromatin remodelling and epigenetic repression of p16INK4A requires the interaction of both EBNA3A and EBNA3C with CtBP. The repression of p16INK4A by latent EBV will not only overcome senescence in infected B cells, but may also pave the way for p16INK4A DNA methylation during B cell lymphomagenesis.

Our immune system is designed to protect us from danger. Upon pathogen invasion and tissue injury, activation of both innate and adaptive immunity enables us to combat infection and to repair tissue damage. Tenascin-C is a large, extracellular matrix glycoprotein that has a very tightly controlled pattern of expression. Little or no tenascin-C is expressed in most healthy adult tissues; however, it is rapidly and transiently induced at sites of tissue injury and infection. Persistent tenascin-C expression is associated with pathologies such as chronic, non-healing wounds, autoimmune diseases, cancer, and fibrotic diseases. We discuss the myriad roles that this multifunctional molecule plays during the immune response, with a focus on how tissue levels of tenascin-C are regulated and the consequences of misregulated tenascin-C expression in immune regulated disease pathogenesis.

Objective. Rheumatoid arthritis is characterized by persistent synovial inflammation and progressive joint destruction, which are mediated by innate and adaptive immune responses. Cytokine blockade successfully treats some patient subsets; however, ϳ50% do not respond to this approach. Targeting of pathogenic T lymphocytes is emerging as an effective alternative/ complementary therapeutic strategy, yet the factors that control T cell activation in joint disease are not well understood. Tenascin-C is an arthritogenic extracellular matrix glycoprotein that is not expressed in healthy synovium but is elevated in the rheumatoid joint, where high levels are produced by myeloid cells. Among these cells, tenascin-C expression is most highly induced in activated dendritic cells (DCs). The aim of this study was to examine the role of tenascin-C in this cell type.Methods. We systematically compared the phenotype of DCs isolated from wild-type mice or mice with a targeted deletion of tenascin-C by assessing cell maturation, cytokine synthesis, and T cell polarization.Results. Dendritic cells derived from tenascin-Cnull mice exhibited no defects in maturation; induction of the class II major histocompatibility complex and the costimulatory molecules CD40 and CD86 was unimpaired. Dendritic cells that did not express tenascin-C, however, produced lower levels of inflammatory cytokines than did cells from wild-type mice and exhibited specific defects in Th17 cell polarization. Moreover, tenascin-C-null mice displayed ablated levels of interleukin-17 in the joint during experimental arthritis.Conclusion. These data demonstrate that tenascin-C is important in DC-mediated polarization of Th17 lymphocytes during inflammation and suggest a key role for this endogenous danger signal in driving adaptive immunity in erosive joint disease.

TNC up-regulates IL-6 expression in human CMF, an effect mediated through the FBG domain of TNC and via the TLR4 receptor.

Introduction The extracellular matrix is a complex, three-dimensional network of secreted molecules that provides structural support to tissues and environmental cues to the cells within. One particular subset of matrix molecules is specifically expressed upon tissue damage. These molecules contribute to effective tissue repair by orchestrating the behaviour of cells that mediate this process, and once the repair is complete, the expression of this matrix is down-regulated. Here, we focus on the recent data that highlights a direct role for injury-induced matrix molecules in driving inflammation upon tissue damage and propose that this matrix creates a specific microenvironment or 'pro-inflammatory niche' that is permissive for localized inflammation during repair. We also examine the evidence indicating that this niche exists, and persists, in the damaged joint of rheumatoid arthritis patients. Finally, we assess the data which demonstrate that these matrix molecules actively contribute to maintaining chronic inflammation during disease progression. Conclusion Together these findings imply that targeting the pro-inflammatory niche in the joint may provide a novel treatment strategy for rheumatoid arthritis.