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ABSTRACT: Systemic lupus erythematosus is a potentially fatal autoimmune disease. Although interleukin-17 (IL-17) has been linked to human lupus and mouse models of this disease, it has not been addressed whether this cytokine plays a critical role in fatal lupus pathology. Here we have demonstrated that increased production of IL-17 cytokines and their signaling via the adaptor protein CIKS (a.k.a. Traf3ip2, Act1) critically contributed to lethal pathology in an FcgammaR2b-deficient mouse model of lupus. Mice lacking IL-17 and especially those lacking CIKS showed greatly improved survival and were largely protected from development of glomerulonephritis. Importantly in this model, potential effects of IL-17 cytokines on antibody production could be distinguished from critical local contributions in kidneys, including recruitment of neutrophils and monocytes. These findings provide the proof of principle that signaling by IL-17 family cytokines mediated via CIKS presents promising therapeutic targets for the treatment of systemic lupus erythematosus, especially in cases with kidney involvement.
Immunity 10/2012; · 21.64 Impact Factor
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ABSTRACT: Psoriasis is a relapsing skin disease characterized by abnormal keratinocyte proliferation and differentiation and by an influx of inflammatory immune cells. Recently, IL-17 cytokines have been strongly implicated as critical for the pathogenesis of this disease. IL-17A (also known as IL-17) and IL-17F are the signature cytokines of Th17 cells, but are also produced by innate cells, including γδ T cells present in skin, whereas epithelial cells, including keratinocytes, may produce IL-17C. IL-17 cytokines signal via the adaptor protein connection to IκB kinase and stress-activated protein kinases (CIKS)/Act1. Psoriasis is a disease with a strong genetic predisposition, and the gene encoding CIKS has recently been identified as a susceptibility locus. Unexpectedly, one predisposing gene variant features a mutation that impairs rather than enhances CIKS-mediated IL-17 cytokine signaling, counter to the predicted role for IL-17 cytokines in psoriatic inflammation. In this study, we demonstrate, however, that this mutant adaptor does not impair the IL-17-specific contributions to the genetic response when combined with TNF-α, a cytokine also prominent in psoriatic inflammation. Interestingly, TNF-α signals compensate IL-17 signaling defects imposed by this mutant adaptor even for genes that are not induced by TNF-α alone, including the transcription factors CCAAT/enhancer binding protein δ and IκBζ, which help regulate secondary gene expression in response to IL-17. Based on these findings we discuss a scenario in which the mutant adaptor may interfere with homeostatic maintenance of epithelial barriers, thereby potentially enabling the initiation of inflammatory responses to insults, whereas this same mutant adaptor would still be able to mediate IL-17-specific contributions to inflammation once TNF-α is present.
The Journal of Immunology 05/2012; 188(12):5906-14. · 5.79 Impact Factor
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ABSTRACT: Cerebral cavernous malformations (CCM) are irregularly shaped and enlarged capillaries in the brain that are prone to hemorrhage, resulting in headaches, seizures, strokes and even death in patients. The disease affects up to 0.5% of the population and the inherited form has been linked to mutations in one of three genetic loci, CCM1, CCM2 and CCM3. To understand the pathophysiology underlying the vascular lesions in CCM, it is critical to develop a reproducible mouse genetic model of this disease. Here, we report that limited conditional ablation of Ccm2 in young adult mice induces observable neurological dysfunction and reproducibly results in brain hemorrhages whose appearance is highly reminiscent of the lesions observed in human CCM patients. We first demonstrate that conventional or endothelial-specific deletion of Ccm2 leads to fatal cardiovascular defects during embryogenesis, including insufficient vascular lumen formation as well as defective arteriogenesis and heart malformation. These findings confirm and extend prior studies. We then demonstrate that the inducible deletion of Ccm2 in adult mice recapitulates the CCM-like brain lesions in humans; the lesions display disrupted vascular lumens, enlarged capillary cavities, loss of proper neuro-vascular associations and an inflammatory reaction. The CCM lesions also exhibit damaged neuronal architecture, the likely cause of neurologic defects, such as ataxia and seizure. These mice represent the first CCM2 animal model for CCM and should provide the means to elucidate disease mechanisms and evaluate therapeutic strategies for human CCM.
Human Molecular Genetics 06/2011; 20(16):3198-206. · 7.64 Impact Factor
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ABSTRACT: Interleukin-17 (IL-17) is essential in host defense against extracellular bacteria and fungi, especially at mucosal sites,
but it also contributes significantly to inflammatory and autoimmune disease pathologies. Binding of IL-17 to its receptor
leads to recruitment of adaptor protein CIKS/Act1 via heterotypic association of their respective SEFIR domains and activation
of transcription factor NF-κB; it is not known whether CIKS and/or NF-κB are required for all gene induction events. Here
we report that CIKS is essential for all IL-17-induced immediate-early genes in primary mouse embryo fibroblasts, whereas
NF-κB is profoundly involved. We also identify a novel subdomain in the N terminus of CIKS that is essential for IL-17-mediated
NF-κB activation. This domain is both necessary and sufficient for interaction between CIKS and TRAF6, an adaptor required
for NF-κB activation. The ability of decoy peptides to block this interaction may provide a new therapeutic strategy for intervention
in IL-17-driven autoimmune and inflammatory diseases.
Journal of Biological Chemistry 04/2011; 286(15):12881-12890. · 4.77 Impact Factor
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[show abstract]
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ABSTRACT: Interleukin-17 (IL-17) is essential in host defense against extracellular bacteria and fungi, especially at mucosal sites,
but it also contributes significantly to inflammatory and autoimmune disease pathologies. Binding of IL-17 to its receptor
leads to recruitment of the adaptor protein CIKS/Act1 via heterotypic association of their respective SEFIR domains and to
activation of the transcription factor NF-κB; it is not known whether CIKS and/or NF-κB are required for all gene induction
events. Here we report that CIKS is essential for all IL-17 induced immediate-early genes in primary mouse embryo fibroblasts,
while NF-κB is profoundly involved. We also identify a novel sub-domain in the N-terminus of CIKS that is essential for IL-17-mediated
NF-κB activation. This domain is both necessary and sufficient for the interaction between CIKS and TRAF6, an adaptor required
for NF-κB activation. The ability of decoy peptides to block this interaction may provide a new therapeutic strategy for
intervention in IL-17-driven autoimmune and inflammatory diseases.
Journal of Biological Chemistry 02/2011; · 4.77 Impact Factor
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[show abstract]
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ABSTRACT: Interleukin-17 (IL-17) is essential in host defense against extracellular bacteria and fungi, especially at mucosal sites, but it also contributes significantly to inflammatory and autoimmune disease pathologies. Binding of IL-17 to its receptor leads to recruitment of adaptor protein CIKS/Act1 via heterotypic association of their respective SEFIR domains and activation of transcription factor NF-κB; it is not known whether CIKS and/or NF-κB are required for all gene induction events. Here we report that CIKS is essential for all IL-17-induced immediate-early genes in primary mouse embryo fibroblasts, whereas NF-κB is profoundly involved. We also identify a novel subdomain in the N terminus of CIKS that is essential for IL-17-mediated NF-κB activation. This domain is both necessary and sufficient for interaction between CIKS and TRAF6, an adaptor required for NF-κB activation. The ability of decoy peptides to block this interaction may provide a new therapeutic strategy for intervention in IL-17-driven autoimmune and inflammatory diseases.
Journal of Biological Chemistry 02/2011; 286(15):12881-90. · 4.77 Impact Factor
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ABSTRACT: Bcl-3 is an atypical member of the IκB family that has the potential to positively or negatively modulate nuclear NF-κB activity in a context-dependent manner. Bcl-3's biologic impact is complex and includes roles in tumorigenesis and diverse immune responses, including innate immunity. Bcl-3 may mediate LPS tolerance, suppressing cytokine production, but it also seems to contribute to defense against select systemic bacterial challenges. However, the potential role of Bcl-3 in organ-specific host defense against bacteria has not been addressed. In this study, we investigated the relevance of Bcl-3 in a lung challenge with the Gram-negative pathogen Klebsiella pneumoniae. In contrast to wild-type mice, Bcl-3-deficient mice exhibited significantly increased susceptibility toward K. pneumoniae pneumonia. The mutant mice showed increased lung damage marked by neutrophilic alveolar consolidation, and they failed to clear bacteria in lungs, which correlated with increased bacteremic dissemination. Loss of Bcl-3 incurred a dramatic cytokine imbalance in the lungs, which was characterized by higher levels of IL-10 and a near total absence of IFN-γ. Moreover, Bcl-3-deficient mice displayed increased lung production of the neutrophil-attracting chemokines CXCL-1 and CXCL-2. Alveolar macrophages and neutrophils are important to antibacterial lung defense. In vitro stimulation of Bcl-3-deficient alveolar macrophages with LPS or heat-killed K. pneumoniae recapitulated the increase in IL-10 production, and Bcl-3-deficient neutrophils were impaired in intracellular bacterial killing. These findings suggest that Bcl-3 is critically involved in lung defense against Gram-negative bacteria, modulating functions of several cells to facilitate efficient clearance of bacteria.
The Journal of Immunology 02/2011; 186(4):2412-21. · 5.79 Impact Factor
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ABSTRACT: CIKS/ACT1 is an adaptor molecule that is necessary for signaling by members of the interleukin-17 cytokine family. The aim of this study was to determine whether this adaptor is required for the initiation of collagen-induced arthritis (CIA). If it is required, then CIKS-mediated signaling could be a potential target for therapeutic intervention in patients with rheumatoid arthritis (RA).
CIA model studies were performed with CIKS-deficient and CIKS-sufficient mice on an otherwise wild-type (WT) C57BL/6 background or on a C57BL/6 background lacking Fcγ receptor IIb (FcγRIIb). In addition, collagen antibody-induced arthritis (CAIA) studies were performed in WT and CIKS-deficient mice. Pathologic changes of arthritis were evaluated by visual inspection of the paws, by histochemical analysis of tissue sections, and by measurements of collagen-specific antibodies.
Pathologic changes of CIA were readily induced in WT mice, with exacerbation of the changes in FcγRIIb-deficient mice. In contrast, CIKS-deficient mice were protected from all aspects of CIA pathology, even on an FcγRIIb-deficient background. The absence of CIKS completely prevented neutrophil infiltration into joints, bone erosion, and cartilage damage; furthermore, the production of type II collagen (CII)-specific antibodies was reduced. In contrast to the CIA model, CIKS-deficient mice in the CAIA model remained susceptible to arthritis.
CIKS-mediated signaling is necessary for the pathogenesis of CIA, but not CAIA. These findings suggest critical functions of CIKS during the development of arthritis in the CIA model, including in the formation of CII antibodies, and they mark the CIKS adaptor as a potential therapeutic target in RA.
Arthritis & Rheumatism 11/2010; 62(11):3334-44. · 7.87 Impact Factor
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ABSTRACT: The NF-kappaB transcription factors have many essential functions in B cells, such as during differentiation and proliferation of Ag-challenged mature B cells, but also during final maturation of developing B cells in the spleen. Among the various specific functions NF-kappaB factors carry out in these biologic contexts, their ability to assure the survival of mature and maturing B cells in the periphery stands out. Less clear is what if any roles NF-kappaB factors play during earlier stages of B cell development in the bone marrow. Using mice deficient in both NF-kappaB1 and NF-kappaB2, which are thus partially compromised in both the classical and alternative activation pathways, we demonstrate a B cell-autonomous contribution of NF-kappaB to the survival of immature B cells in the bone marrow. NF-kappaB1 and NF-kappaB2 also play a role during the earlier transition from proB to late preB cells; however, in this context these factors do not act in a B cell-autonomous fashion. Although NF-kappaB1 and NF-kappaB2 are not absolutely required for survival and progression of immature B cells in the bone marrow, they nevertheless make a significant contribution that marks the beginning of the profound cell-autonomous control these factors exert during all subsequent stages of B cell development. Therefore, the lifelong dependency of B cells on NF-kappaB-mediated survival functions is set in motion at the time of first expression of a full BCR.
The Journal of Immunology 04/2009; 182(6):3406-13. · 5.79 Impact Factor
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Estefania Claudio,
Søren Ulrik Sønder,
Sun Saret,
Gabrielle Carvalho,
Thirumalai R Ramalingam,
Thomas A Wynn,
Alain Chariot,
Antonio Garcia-Perganeda,
Antonio Leonardi,
Andrea Paun,
Amy Chen,
Nina Y Ren,
Hongshan Wang, Ulrich Siebenlist
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ABSTRACT: IL-17 is the signature cytokine of recently discovered Th type 17 (Th17) cells, which are prominent in defense against extracellular bacteria and fungi as well as in autoimmune diseases, such as rheumatoid arthritis and experimental autoimmune encephalomyelitis in animal models. IL-25 is a member of the IL-17 family of cytokines, but has been associated with Th2 responses instead and may negatively cross-regulate Th17/IL-17 responses. IL-25 can initiate an allergic asthma-like inflammation in the airways, which includes recruitment of eosinophils, mucus hypersecretion, Th2 cytokine production, and airways hyperreactivity. We demonstrate that these effects of IL-25 are entirely dependent on the adaptor protein CIKS (also known as Act1). Surprisingly, this adaptor is necessary to transmit IL-17 signals as well, despite the very distinct biologic responses that these two cytokines elicit. We identify CD11c(+) macrophage-like lung cells as physiologic relevant targets of IL-25 in vivo.
The Journal of Immunology 03/2009; 182(3):1617-30. · 5.79 Impact Factor
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Catherine Creppe,
Lina Malinouskaya,
Marie-Laure Volvert,
Magali Gillard,
Pierre Close,
Olivier Malaise,
Sophie Laguesse,
Isabelle Cornez,
Souad Rahmouni,
Sandra Ormenese,
Shibeshih Belachew,
Brigitte Malgrange,
Jean-Paul Chapelle, Ulrich Siebenlist,
Gustave Moonen,
Alain Chariot,
Laurent Nguyen
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ABSTRACT: The generation of cortical projection neurons relies on the coordination of radial migration with branching. Here, we report that the multisubunit histone acetyltransferase Elongator complex, which contributes to transcript elongation, also regulates the maturation of projection neurons. Indeed, silencing of its scaffold (Elp1) or catalytic subunit (Elp3) cell-autonomously delays the migration and impairs the branching of projection neurons. Strikingly, neurons defective in Elongator show reduced levels of acetylated alpha-tubulin. Reduction of alpha-tubulin acetylation via expression of a nonacetylatable alpha-tubulin mutant leads to comparable defects in cortical neurons and suggests that alpha-tubulin is a target of Elp3. This is further supported by the demonstration that Elp3 promotes acetylation and counteracts HDAC6-mediated deacetylation of this substrate in vitro. Our results uncover alpha-tubulin as a target of the Elongator complex and suggest that a tight regulation of its acetylation underlies the maturation of cortical projection neurons.
Cell 02/2009; 136(3):551-64. · 32.40 Impact Factor
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ABSTRACT: Nuclear factor-kappaB (NF-kappaB) is an inducible transcription factor controlled by two principal signaling cascades, each activated by a set of signal ligands: the classical/canonical NF-kappaB activation pathway and the alternative/noncanonical pathway. The former pathway proceeds via phosphorylation and degradation of inhibitor of NF-kappaB (IkappaB) and leads most commonly to activation of the heterodimer RelA/NF-kappaB1(p50). The latter pathway proceeds via phosphorylation and proteolytic processing of NF-kappaB2 (p100) and leads to activation, most commonly, of the heterodimer RelB/NF-kappaB2 (p52). Both pathways play critical roles at multiple levels of the immune system in both health and disease, including the autoimmune inflammatory response. These roles include cell cycle progression, cell survival, adhesion, and inhibition of apoptosis. NF-kappaB is constitutively activated in many autoimmune diseases, including diabetes type 1, systemic lupus erythematosus, and rheumatoid arthritis (RA). In this review we survey recent developments in the involvement of the classical and alternative pathways of NF-kappaB activation in autoimmunity, focusing particularly on RA. We discuss the involvement of NF-kappaB in self-reactive T and B lymphocyte development, survival and proliferation, and the maintenance of chronic inflammation due to cytokines such as tumor necrosis factor-alpha, IL-1, IL-6, and IL-8. We discuss the roles played by IL-17 and T-helper-17 cells in the inflammatory process; in the activation, maturation, and proliferation of RA fibroblast-like synovial cells; and differentiation and activation of osteoclast bone-resorbing activity. The prospects of therapeutic intervention to block activation of the NF-kappaB signaling pathways in RA are also discussed.
Arthritis research & therapy 09/2008; 10(4):212. · 4.27 Impact Factor
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Jean-Stéphane Gatot,
Romain Gioia,
Tieu-Lan Chau,
Félicia Patrascu,
Michael Warnier,
Pierre Close,
Jean-Paul Chapelle,
Eric Muraille,
Keith Brown, Ulrich Siebenlist,
Jacques Piette,
Emmanuel Dejardin,
Alain Chariot
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ABSTRACT: Type I interferon gene induction relies on IKK-related kinase TBK1 and IKKepsilon-mediated phosphorylations of IRF3/7 through the Toll-like receptor-dependent signaling pathways. The scaffold proteins that assemble these kinase complexes are poorly characterized. We show here that TANK/ITRAF is required for the TBK1- and IKKepsilon-mediated IRF3/7 phosphorylations through some Toll-like receptor-dependent pathways and is part of a TRAF3-containing complex. Moreover, TANK is dispensable for the early phase of double-stranded RNA-mediated IRF3 phosphorylation. Interestingly, TANK is heavily phosphorylated by TBK1-IKKepsilon upon lipopolysaccharide stimulation and is also subject to lipopolysaccharide- and TBK1-IKKepsilon-mediated Lys(63)-linked polyubiquitination, a mechanism that does not require TBK1-IKKepsilon kinase activity. Thus, we have identified TANK as a scaffold protein that assembles some but not all IRF3/7-phosphorylating TBK1-IKKepsilon complexes and demonstrated that these kinases possess two functions, namely the phosphorylation of both IRF3/7 and TANK as well as the recruitment of an E3 ligase for Lys(63)-linked polyubiquitination of their scaffold protein, TANK.
Journal of Biological Chemistry 11/2007; 282(43):31131-46. · 4.77 Impact Factor
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Jean-Stéphane Gatot,
Romain Gioia,
Tieu-Lan Chau,
Félicia Patrascu,
Michael Warnier,
Pierre Close,
Jean-Paul Chapelle,
Eric Muraille,
Keith Brown, Ulrich Siebenlist,
Jacques Piette,
Emmanuel Dejardin,
Alain Chariot
[show abstract]
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ABSTRACT: Type I interferon gene induction relies on IKK-related kinase TBK1 and IKKϵ-mediated phosphorylations of IRF3/7 through the
Toll-like receptor-dependent signaling pathways. The scaffold proteins that assemble these kinase complexes are poorly characterized.
We show here that TANK/ITRAF is required for the TBK1- and IKKϵ-mediated IRF3/7 phosphorylations through some Toll-like receptor-dependent
pathways and is part of a TRAF3-containing complex. Moreover, TANK is dispensable for the early phase of double-stranded RNA-mediated
IRF3 phosphorylation. Interestingly, TANK is heavily phosphorylated by TBK1-IKKϵ upon lipopolysaccharide stimulation and is
also subject to lipopolysaccharide- and TBK1-IKKϵ-mediated Lys63-linked polyubiquitination, a mechanism that does not require TBK1-IKKϵ kinase activity. Thus, we have identified TANK as
a scaffold protein that assembles some but not all IRF3/7-phosphorylating TBK1-IKKϵ complexes and demonstrated that these
kinases possess two functions, namely the phosphorylation of both IRF3/7 and TANK as well as the recruitment of an E3 ligase
for Lys63-linked polyubiquitination of their scaffold protein, TANK.
Journal of Biological Chemistry 10/2007; 282(43):31131-31146. · 4.77 Impact Factor
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ABSTRACT: Bcl-3 is a member of the family of IkappaB inhibitors. Unlike the classical, cytoplasmic IkappaBs, Bcl-3 does not inhibit RelA- or c-Rel-containing NF-kappaB transcription factor dimers. Instead, Bcl-3 can enter the nucleus and modulate NF-kappaB activity, although the underlying mechanism and physiologic function remain largely unknown. Here we identified Bcl-3 as a regulator of immunologic tolerance to self. In parallel with NF-kappaB2, Bcl-3 functions within stroma to generate medullary thymic epithelial cells, which are essential for negative selection of autoreactive T cells. Loss of both NF-kappaB2 and Bcl-3, but not either one alone, led to a profound breakdown in central tolerance resulting in rapid and fatal multiorgan inflammation. These data reveal extensive utilization of the NF-kappaB system to promote central tolerance in the thymus, in apparent contrast with the well-known roles of NF-kappaB to promote inflammation and autoimmunity in the periphery.
Immunity 10/2007; 27(3):438-52. · 21.64 Impact Factor
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ABSTRACT: In mice, acquisition of Ly49 receptors characterizes one of the developmental stages of NK cells. We previously described a novel Ly49 promoter, Pro1, involved in Ly49 gene regulation in immature NK cells. Pro1 transcriptional activity requires a NF-kappaB binding site; however, only NF-kappaB/p50 binding to this element was observed. Cotransfection of NF-kappaB/p65 with Ly49g Pro1 in LNK cells induced a decrease in the transcriptional activity of the core promoter. Moreover, decreasing NF-kappaB/p65 protein expression by RNA interference increases Pro1 transcriptional activity. A high rate of NF-kappaB/p65 degradation in LNK cells correlates with Pro1 activity, since treatment with the proteasome inhibitor MG132 increased levels of NF-kappaB/p65 protein and decreased Pro1 activity. In addition, analysis of the Ly49 repertoire in NF-kappaB/p50 null mice reveals a decrease in the proportion of NK cells expressing a given Ly49 molecule. The defect in Ly49 expression is observed in the bone marrow and the spleen with a similar altered pattern of developmental stages in each tissue. The frequency of Ly49 expression in NF-kappaB/p52 null mice is slightly increased, indicating the specific role of NF-kappaB/p50 in Ly49 gene activation. These results suggest that NF-kappaB p50/p65 plays a major role in the initiation of Ly49 gene expression in NK cells.
The Journal of Immunology 09/2007; 179(3):1751-9. · 5.79 Impact Factor
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ABSTRACT: CD97 is a member of the adhesion family of G protein-coupled receptors. Alternatively spliced forms of CD97 bind integrins alpha5beta1 and alphavbeta3, decay accelerating factor, or dermatan sulfate. CD97 is expressed on myeloid cells at high levels and a variety of other cell types at lower levels. Little is known about the physiological function of CD97. To begin dissecting the function of CD97, we evaluated the immune response of CD97 null mice to systemic infection by Listeria monocytogenes. CD97 null mice were significantly more resistant to listeriosis than matched wild-type mice. A major determinant of the difference in survival appeared to be the comparatively more robust accumulation of granulocytes in the blood and in infected livers of CD97 null mice within 18 h of inoculation, correlating with a decrease in the number of bacteria. CD97 null mice also displayed a mild granulocytosis in the nonchallenged state. Because there is a strong suggestion that CD97 functions in an adhesive capacity, we examined the migratory properties of granulocytes in CD97 null mice. In chimeric animals, CD97 null and wild-type granulocytes migrated similarly, as determined by inflammation-induced emigration from the bone marrow and accumulation in the peritoneum. Granulocyte development in the bone marrow of CD97 null mice was comparable to that of wild-type mice, and CD97 deficiency did not appear to stimulate granulocytosis secondary to peripheral inflammation and resultant granulocyte colony-stimulating factor induction, unlike various other models of adhesion deficiencies. Our results suggest that CD97 plays a role in peripheral granulocyte homeostasis.
Infection and Immunity 04/2007; 75(3):1144-53. · 4.16 Impact Factor
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02/2007: pages 51-69;
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Pierre Close,
Nicola Hawkes,
Isabelle Cornez,
Catherine Creppe,
Charles A Lambert,
Bernard Rogister, Ulrich Siebenlist,
Marie-Paule Merville,
Susan A Slaugenhaupt,
Vincent Bours,
Jesper Q Svejstrup,
Alain Chariot
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ABSTRACT: Mutations in IKBKAP, encoding a subunit of Elongator, cause familial dysautonomia (FD), a severe neurodevelopmental disease with complex clinical characteristics. Elongator was previously linked not only with transcriptional elongation and histone acetylation but also with other cellular processes. Here, we used RNA interference (RNAi) and fibroblasts from FD patients to identify Elongator target genes and study the role of Elongator in transcription. Strikingly, whereas Elongator is recruited to both target and nontarget genes, only target genes display histone H3 hypoacetylation and progressively lower RNAPII density through the coding region in FD cells. Interestingly, several target genes encode proteins implicated in cell motility. Indeed, characterization of IKAP/hELP1 RNAi cells, FD fibroblasts, and neuronal cell-derived cells uncovered defects in this cellular function upon Elongator depletion. These results indicate that defects in Elongator function affect transcriptional elongation of several genes and that the ensuing cell motility deficiencies may underlie the neuropathology of FD patients.
Molecular Cell 06/2006; 22(4):521-31. · 14.18 Impact Factor
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ABSTRACT: The evolutionarily conserved nuclear factor-kappaB family of transcription factors is known to have a crucial role in rapid responses to stress and pathogens, inducing transcription of many genes that are essential for host defence. Now, studies of mice that are deficient in nuclear factor-kappaB-family members (or deficient in the activation of these factors) reveal that nuclear factor-kappaB is extensively involved in the development of T cells and B cells. And, as we review here, although these factors have several roles, their primary cell-autonomous function is to ensure lymphocyte survival at various developmental stages. This function is subverted in numerous diseases and can lead, for example, to survival of self-reactive lymphocytes or tumour cells.
Nature reviews. Immunology 07/2005; 5(6):435-45. · 33.29 Impact Factor
