Anticancer Activity and Mechanisms of Action of MAPK pathway inhibitors

Treg cells numbers in the lamina propria (LP) were not affected by miR-17 or Eos over-expression (Figure 6D, red bars)

Treg cells numbers in the lamina propria (LP) were not affected by miR-17 or Eos over-expression (Figure 6D, red bars). al., 2006; Yang et al., 2008a; Zhou et al., 2008a), it can also inhibit the ability of natural Treg cells to suppress T cell proliferation (Goodman et al., 2009; Shen and Goldstein, 2009). Although IL-6 mediated inhibition of Foxp3 expression (Gao et al., 2012; Lal et al., 2009; Yang et al., 2008b; Zheng et al., 2008) may account for some of this antagonism, it is possible that IL-6 may impact other molecules important for Treg cell suppressive function. Foxp3 Cefepime Dihydrochloride Monohydrate cooperates with a cadre of co-factors to shape the transcriptional landscape of Treg cells (Fu et al., 2012; Rudra et al., 2012). One such co-regulator, Eos, is essential for Foxp3-mediated control of Treg cell gene expression (i.e. repression of effector T cell genes) and function (Pan et al., 2009). While Treg cells contain high amounts of Eos, only low levels are detected in Th17 cells (Quintana et al., 2012). Furthermore, a subset of reprogrammed Treg cells appears prone to loss of Cefepime Dihydrochloride Monohydrate Eos expression (Sharma et al., 2013). This suggests that Eos is tightly regulated in developing Treg cells as well as those undergoing conversion to an expanded or Teff cell-like phenotype. Other transcriptional regulators associated with Foxp3 activity include IRF-4 (Zheng et al., 2009), Satb1 (Fu et al., 2012; Rudra et al., 2012), and GATA-1 (Fu et al., 2012). These molecules could share partially redundant co-repressor function that assures silencing of Teff cell genes in Foxp3+ Treg cells (Bettini et al., 2012; Darce et al., 2012; Fu et al., 2012). The mechanisms that regulate the expression of Eos and other co-regulators of Foxp3 activity in Treg cells are not well understood. MicroRNAs (miRNAs ) impact aspects of immunity, including the function, homeostasis and phenotypic stability of Treg cells (OConnell et al., 2010). MiRNAs are short (~22 nucleotide), non-coding RNAs produced via sequential processing of primary RNA polymerase II transcripts by the class III RNase enzymes Drosha and Dicer. MiRNAs act on target protein-encoding mRNAs through the RNA-induced silencing complex, marking them for translational repression or degradation (Stefani and Slack, 2008). Different miRNA clusters have been shown to be involved in the immune response (Hou et al., 2009; Li et al., 2007; Xiao et al., 2008; Zhou et al., 2008b). Deletion of and in Treg cells results in autoimmunity similar to that seen in Scurfy (Foxp3 null) mice although Foxp3 expression levels are not significantly changed (Chong et al., 2008; Liston et al., 2008). Several miRNAs contribute to Treg cell function and phenotypic stability. For instance, miR-146a promotes Treg-mediated control of Th1 responses (Lu et al., 2010); miR-10a prevents acquisition of a Th17-like phenotype by Treg cells (Takahashi et al., 2012); and miR-155 supports Treg cell homeostasis and expansion (Lu et al., 2009) as well as their development (Kohlhaas et al., 2009). The miR-17-92 miRNA Cefepime Dihydrochloride Monohydrate cluster has been implicated in immune Cefepime Dihydrochloride Monohydrate regulation and lymphomagenesis. The gene encoding this cluster is located on human chromosome 13q31, in a genomic region that is often amplified in lymphomas, and other cancers that also have high expression of the mature miRNAs of this locus (Ota et al., 2004; Tagawa and Seto, 2005). The inflammatory cytokine IL-6 induces miR-17-92 expression (Brock et al., 2009), and ectopic expression of the miR-17-92 cluster in T cells causes autoimmunity in mice (Xiao et al., 2008). Studies of miR-17-92 deficient mice have implicated these miRNAs in the regulation of Teff and Treg cell function. One study found that members of this cluster promote Rabbit Polyclonal to PTGER2 IFN production by Th1 cells while suppressing the differentiation of iTregs (Jiang et al., 2011). Another found that miR-17-92 deficient T cells were less pathogenic than wild type cells in a model of.