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Trends Mol Med,
2007]
Transforming growth factor beta1 (TGFbeta1), an important pleiotropic, immunoregulatory cytokine, uses distinct signaling mechanisms in lymphocytes to affect T-cell homeostasis, regulatory T (T(reg))-cell and effector-cell function and tumorigenesis. Defects in TGFbeta1 expression or its signaling in T cells correlate with the onset of several autoimmune diseases. TGFbeta1 prevents abnormal T-cell activation through the modulation of Ca(2+)-calcineurin signaling in a Caenorhabditis elegans Sma and Drosophila Mad proteins (SMAD)3 and SMAD4-independent manner; however, in T(reg) cells, its effects are mediated, at least in part, through SMAD signaling. TGFbeta1 also acts as a pro-inflammatory cytokine and induces interleukin (IL)-17-producing pathogenic T-helper cells (T(h) IL-17 cells) synergistically during an inflammatory response in which IL-6 is produced. Here, we will review TGFbeta1 and its signaling in T cells with an emphasis on the regulatory arm of immune tolerance.
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Int J Parasitol,
2003]
Parasitic nematodes, living in the intestinal tract or within tissues of theirs hosts, are constantly exposed to an array of immune effector mechanisms. One strategy to cope with the immune response is the release of immunomodulatory components that block effector mechanisms or interact with the cytokine network. Among the secreted nematode immunomodulators, cysteine protease inhibitors (cystatins) are shown to be of major importance. Nematode cystatins inhibit, among others, proteases involved in antigen processing and presentation, which leads to a reduction of T cell responses. At the same time nematode cystatins modulate cytokine responses, the most prominent trait being the upregulation of IL-10, a Th2 cytokine, by macrophages. In this situation, IL-10 leads among others to downregulation of costimulatory surface molecules of macrophages. These properties contribute to induction of an anti-inflammatory environment, concomitant with a strong inhibition of cellular proliferation. This setting is believed to favour the survival of worms. An opposite activity of nematode cystatins is the upregulation of production of inducible nitric oxide by IFN-gamma activated macrophages, an intrinsic property of natural cysteine protease inhibitors. This shows that these proteins can act as proinflammatory molecules under certain circumstances. A comparison of the immunomodulatory effects of cystatins of filarial nematodes with homologous proteins of the free-living nematode Caenorhabditis elegans revealed distinct differences. Caenorhabditis elegans cystatins induce the production of the Th1 cytokine IL-12, in contrast to filarial cystatins that upregulate IL-10. Caenorhabditis elegans cystatins hardly inhibit cellular proliferation. These data suggest that cystatins of parasitic nematodes have multiple, specific capacities for immunomodulation, acting in parallel on different immune effector mechanisms. Elucidation of the mechanisms involved might be useful in the development of immunotherapeutic reagents in the future.
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F1000Res,
2016]
The capacity of an axon to regenerate is regulated by its external environment and by cell-intrinsic factors. Studies in a variety of organisms suggest that alterations in axonal microtubule (MT) dynamics have potent effects on axon regeneration. We review recent findings on the regulation of MT dynamics during axon regeneration, focusing on the nematode Caenorhabditis elegans. In C. elegans the dual leucine zipper kinase (DLK) promotes axon regeneration, whereas the exchange factor for Arf6 (EFA-6) inhibits axon regeneration. Both DLK and EFA-6 respond to injury and control axon regeneration in part via MT dynamics. How the DLK and EFA-6 pathways are related is a topic of active investigation, as is the mechanism by which EFA-6 responds to axonal injury. We evaluate potential candidates, such as the MT affinity-regulating kinase PAR-1/MARK, in regulation of EFA-6 and axonal MT dynamics in regeneration.
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Curr Opin Immunol,
2005]
Genetic and functional genomic approaches have begun to define the molecular determinants of pathogen resistance in Caenorhabditis elegans. Conserved signal transduction components are required for pathogen resistance, including a Toll/IL-1 receptor domain adaptor protein that functions upstream of a conserved
p38 MAP kinase pathway. We suggest that this pathway is an ancestral innate immune signaling pathway present in the common ancestor of nematodes, arthropods and vertebrates, which is likely to predate the involvement of canonical Toll signaling pathways in innate immunity. We anticipate that the study of pathogen resistance in C. elegans will continue to provide evolutionary and mechanistic insights into the signal transduction and physiology of innate immunity.
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Curr Protein Pept Sci,
2003]
ES-62 is a major secreted glycoprotein of the rodent filarial nematode Acanthocheilonema viteae and homologue of molecules found in filarial nematodes which parasitise humans. The molecule consists of a tetramer of apparently identical monomers of ~62 kDa which we have shown by sedimentation equilibrium analytical ultracentrifugation to strongly associate. ES-62 is one of several filarial nematode proteins to contain the unusual post-translational modification of phosphorylcholine (PC) addition. Specifically, we have found that PC is attached to one of three distinct N-type glycans we have characterised on the molecule. The amino acid sequence of ES-62 shows 37-39% identity with a family of 6 other proteins, some of which have been predicted to be amino- or carboxy-peptidases. We have also found that ES-62 is able to interact with a number of cells of the immune system, specifically B- and T-lymphocytes, macrophages and dendritic cells. Lymphocytes exposed to ES-62 in vitro or in vivo are less able to proliferate in response to ligation via the antigen receptor. Peritoneal macrophages pre-exposed to the molecule are less able to produce the cytokines IL-12, IL-6 and TNF-alpha following subsequent incubation with the classical stimulators IFNgamma and LPS. Dendritic cells allowed to mature in the presence of ES-62 acquire a phenotype, which allows them to induce anti-inflammatory "TH2-type" responses. With respect to immunomodulation, the PC moiety of the parasite molecule appears to be predominantly responsible for the effects on lymphocyte proliferation at least and we have also found that its removal converts the murine IgG antibody response to ES-62 from solely IgG1 to mixed IgG1/IgG2a. ES-62 appears to interact with cells of the immune system in a PC-dependent manner and, at least in part, via a molecule of ~82 kDa. Studies of the interaction in lymphocytes show that it is associated with activation of certain signal transduction molecules including a number of protein tyrosine kinases and mitogen activated protein kinases (MAPkinases). Although such activation is insufficient to induce proliferation, it serves to almost completely desensitise the cells to antigen-receptor ligation-induced activation of the phosphoinositide 3-kinase (PI-3-kinase) and Ras/MAPkinase pathways, events critical for lymphocyte proliferation. Such desensitisation reflects ES-62-primed recruitment of a number of negative regulators of these pathways, such as the phosphatases SHP-1 and Pac-1.
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J Clin Med,
2016]
The nematode Caenorhabditis elegans is a powerful model organism to study functions of polyunsaturated fatty acids. The ability to alter fatty acid composition with genetic manipulation and dietary supplementation permits the dissection of the roles of omega-3 and omega-6 fatty acids in many biological process including reproduction, aging and neurobiology. Studies in C. elegans to date have mostly identified overlapping functions of 20-carbon omega-6 and omega-3 fatty acids in reproduction and in neurons, however, specific roles for either omega-3 or omega-6 fatty acids are beginning to emerge. Recent findings with importance to human health include the identification of a conserved Cox-independent prostaglandin synthesis pathway, critical functions for cytochrome P450 derivatives of polyunsaturated fatty acids, the requirements for omega-6 and omega-3 fatty acids in sensory neurons, and the importance of fatty acid desaturation for long lifespan. Furthermore, the ability of C. elegans to interconvert omega-6 to omega-3 fatty acids using the FAT-1 omega-3 desaturase has been exploited in mammalian studies and biotechnology approaches to generate mammals capable of exogenous generation of omega-3 fatty acids.
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Nat Rev Mol Cell Biol,
2015]
DNA N(6)-adenine methylation (N(6)-methyladenine; 6mA) in prokaryotes functions primarily in the host defence system. The prevalence and significance of this modification in eukaryotes had been unclear until recently. Here, we discuss recent publications documenting the presence of 6mA in Chlamydomonas reinhardtii, Drosophila melanogaster and Caenorhabditis elegans; consider possible roles for this DNA modification in regulating transcription, the activity of transposable elements and transgenerational epigenetic inheritance; and propose 6mA as a new epigenetic mark in eukaryotes.
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Trends Neurosci,
2002]
How does an extracellular guidance molecule direct multiple growth cones to different positions? The answer is important for understanding the development of complex neural connections. UNC-6 is a member of the netrin family of guidance proteins. It has phylogenetically conserved domains that mediate its different guidance and branching activities. In the Caenorhabditis elegans embryo, UNC-6 is secreted ventrally and a pattern of circumferential axon tracts develops as pioneer growth cones bearing UNC-5 and UNC-40 receptors are directed towards, or away from,the ventral sources. Following the first migrations, UNC-6 from additional sources allows more complex migration patterns to emerge. In addition, at specific dorsoventral positions, locally restricted extracellular molecules alter growth cone responses to UNC-6, causing circumferentially migrating growth cones to turn and longitudinal nerves to develop. These observations show that extracellular guidance molecules can direct complex arrangements of migrating growth cones in vivo by eliciting different types of responses, by spatially and temporally regulating their expression and by working in concert with other extracellular molecules.
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Nat Rev Mol Cell Biol,
2012]
The centriole is an evolutionarily conserved macromolecular structure that is crucial for the formation of flagella, cilia and centrosomes. The ultrastructure of the centriole was first characterized decades ago with the advent of electron microscopy, revealing a striking ninefold radial arrangement of microtubules. However, it is only recently that the molecular mechanisms governing centriole assembly have begun to emerge, including the elucidation of the crucial role of spindle assembly abnormal 6 (SAS-6) proteins in imparting the ninefold symmetry. These advances have brought the field to an exciting era in which architecture meets function.
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Bioessays,
2002]
E4BP4, a mammalian basic leucine zipper (bZIP) transcription factor, was first identified through its ability to bind and repress viral promoter sequences. Subsequently, E4BP4 and homologues in other species have been implicated in a diverse range of processes including commitment to cell survival versus apoptosis, the anti-inflammatory response and, most recently, in the mammalian circadian oscillatory mechanism. In some of these cases at least, E4BP4 appears to act antagonistically with members of the related PAR family of transcription factors with which it shares DNA-binding specificity. This diversity of function is mirrored by the regulatory pathways impinging on E4BP4, which include regulation by ras via the lymphokine IL-3 in murine B-cells, by thyroid hormone during Xenopus tail resorption, by glucocorticoids in murine fibroblasts and by calcium in rat smooth muscle cells. This article will cover the unfolding role/s of and regulation of E4BP4, E4BP4-like proteins and PAR factors in species as diverse as mouse and C. elegans. Copyright 2002 Wiley-Periodicals, Inc.