Burkly, L. et al. Expression of RelB is required for development of thymic medulla and dendritic cells. Nature 373, 531-536
Biogen Inc., Cambridge, Massachusetts 02142. Nature
(Impact Factor: 41.46).
03/1995; 373(6514):531-6. DOI: 10.1038/373531a0
Dendritic cells (DC) derived from bone marrow are critical in the function of the immune system, for they are the primary antigen-presenting cells in the activation of T-lymphocyte response. Their differentiation from precursor cells has not been defined at a molecular level, but recent studies have shown an association between expression of the relB subunit of the NF-kappa B complex and the presence of DC in specific regions of normal unstimulated lymphoid tissues. Here we show that relB expression also correlates with differentiation of DC in autoimmune infiltrates in situ, and that a mutation disrupting the relB gene results in mice with impaired antigen-presenting cell function, and a syndrome of excess production of granulocytes and macrophages. Thymic UEA-1+ medullary epithelial cells from normal mice show striking similarities to DC and, interestingly, these cells are also absent in relB mutant mice. Taken together, these results suggest that relB is critical in the coordinated activation of genes necessary for the differentiation of two unrelated but phenotypically similar cells (DC and thymic UEA-1+ medullary epithelial cells) and is therefore a candidate for a gene determining lineage commitment in the immune system.
Available from: Cristina M Alvira
- "Mice with targeted deletion of RelB develop chronic inflammation of numerous organs secondary to an impaired ability to clear autoreactive T-cells. In addition to this inflammatory phenotype, these mice also have functional immune defects, demonstrating increased susceptibility to viral and bacterial infections (Burkly et al., 1995; Weih et al., 1995, 1997b). The loss of p50 markedly exaggerates this inflammatory phenotype observed in the relb−/− mice, with relb−/−p50−/− mice dying within the first month of life, suggesting that p50 complexes partially compensate for the absence of RelB (Weih et al., 1997a). "
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ABSTRACT: In contrast to other organs, the lung completes a significant portion of its development after term birth. During this stage of alveolarization, division of the alveolar ducts into alveolar sacs by secondary septation, and expansion of the pulmonary vasculature by means of angiogenesis markedly increase the gas exchange surface area of the lung. However, postnatal completion of growth renders the lung highly susceptible to environmental insults such as inflammation that disrupt this developmental program. This is particularly evident in the setting of preterm birth, where impairment of alveolarization causes bronchopulmonary dysplasia, a chronic lung disease associated with significant morbidity. The nuclear factor κ-B (NFκB) family of transcription factors are ubiquitously expressed, and function to regulate diverse cellular processes including proliferation, survival, and immunity. Extensive evidence suggests that activation of NFκB is important in the regulation of inflammation and in the control of angiogenesis. Therefore, NFκB-mediated downstream effects likely influence the lung response to injury and may also mediate normal alveolar development. This review summarizes the main biologic functions of NFκB, and highlights the regulatory mechanisms that allow for diversity and specificity in downstream gene activation. This is followed by a description of the pro and anti-inflammatory functions of NFκB in the lung, and of NFκB-mediated angiogenic effects. Finally, this review summarizes the clinical and experimental data that support a role for NFκB in mediating postnatal angiogenesis and alveolarization, and discusses the challenges that remain in developing therapies that can selectively block the detrimental functions of NFκB yet preserve the beneficial effects. Birth Defects Research, 2014. © 2014 Wiley Periodicals, Inc.
Available from: Stefanie Trojandt
- "However, neither the expression level of the endogenous NF-κB inhibitor IκB-α , nor the level and activation state of the ubiquitously expressed NF-κB family member p65  were altered in GA-treated MO-DCs. Moreover, expression of the largely APC-restricted NF-κB family member RelB  was actually reduced in this MO-DC population. Therefore, further analysis is required to elucidate whether GA treatment results in activation of NF-κB in unstimulated MO-DCs, and which of the other members of this TF family  may be involved. "
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ABSTRACT: The chaperon heat shock protein 90 (HSP90) constitutes an important target for anti-tumor therapy due to its essential role in the stabilization of oncogenes. However, HSP90 is ubiquitously active to orchestrate protein turnover, chemotherapeutics that target HSP90 may affect immune cells as a significant side effect. Therefore, we asked for potential effects of pharmacological HSP90 inhibition at a therapeutically relevant concentration on human dendritic cells (DCs) as main inducers of both cellular and humoral immune responses, and on human CD4+ T cells as directly activated by DCs and essential to confer B cell help.
Unstimulated human monocyte-derived DCs (MO-DCs) were treated with the prototypical HSP90 inhibitor geldanamycin (GA). Based on dose titration studies performed to assess cytotoxic effects, GA was applied at a rather low concentration, comparable to serum levels of clinically used HSP90 inhibitors. The immuno-phenotype (surface markers, cytokines), migratory capacity, allo T cell stimulatory and polarizing properties (proliferation, cytokine pattern) of GA-treated MO-DCs were assessed. Moreover, effects of GA on resting and differentially stimulated CD4+ T cells in terms of cytotoxicity and proliferation were analysed.
GA induced partial activation of unstimulated MO-DCs. In contrast, when coapplied in the course of MO-DC stimulation, GA prevented the acquisition of a fully mature DC phenotype. Consequently, this MO-DC population exerted lower allo CD4+ T cell stimulation and cytokine production. Furthermore, GA exerted no cytotoxic effect on resting T cells, but abrogated proliferation of T cells stimulated by MO-DCs at either state of activation or by stimulatory antibodies.
HSP90 inhibitors at clinically relevant concentrations may modulate adaptive immune responses both on the level of DC activation and T cell proliferation. Surprisingly, unstimulated DCs may be partially activated by that agent. However, due to the potent detrimental effects of HSP90 inhibitors on stimulated CD4+ T cells, as an outcome a patients T cell responses might be impaired. Therefore, HSP90 inhibitors most probably are not suitable for treatment in combination with immunotherapeutic approaches aimed to induce DC/T cell activation.
Available from: Yong Zhao
- "IKKα is phosphorylated by NIK and in turn triggers p100 partial degradation to p52 and then translocation to the nucleus together with RelB. Mice deficient of genes in nonclassical NF-κB pathways including NIK, IKKα, and RelB had abnormal thymus development with reduced UEA-1+ and/or Aire+ mTECs [60–64]. p52 deficiency results in less significant damage with little reduction in UEA-1+ and CD80hi mTEC but with no obvious medullary architecture changes . "
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ABSTRACT: Thymic epithelial cells (TECs) are the key components in thymic microenvironment for T cells development. TECs, composed of cortical and medullary TECs, are derived from a common bipotent progenitor and undergo a stepwise development controlled by multiple levels of signals to be functionally mature for supporting thymocyte development. Tumor necrosis factor receptor (TNFR) family members including the receptor activator for NF κ B (RANK), CD40, and lymphotoxin β receptor (LT β R) cooperatively control the thymic medullary microenvironment and self-tolerance establishment. In addition, fibroblast growth factors (FGFs), Wnt, and Notch signals are essential for establishment of functional thymic microenvironment. Transcription factors Foxn1 and autoimmune regulator (Aire) are powerful modulators of TEC development, differentiation, and self-tolerance. Dysfunction in thymic microenvironment including defects of TEC and thymocyte development would cause physiological disorders such as tumor, infectious diseases, and autoimmune diseases. In the present review, we will summarize our current understanding on TEC development and the underlying molecular signals pathways and the involvement of thymus dysfunction in human diseases.
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