DC apoptosis has been observed in patients with cancer and sepsis, and defects in DC apoptosis have been implicated in the development of autoimmune diseases. However, the mechanisms of how DC apoptosis affects immune responses, are unclear. In this study, we showed that immature viable DC have the ability to uptake apoptotic DC as well as necrotic DC without it being recognized as an inflammatory event by immature viable DC. However, the specific uptake of apoptotic DC converted immature viable DC into tolerogenic DC, which were resistant to LPS-induced maturation. These tolerogenic DC secreted increased levels of TGF-b1, which induced differentiation of naïve T cells into Foxp3 1 Treg. Furthermore, induction of Treg differentiation only occurred upon uptake of apoptotic DC and not apoptotic splenocytes by viable DC, indicating that it is specifically the uptake of apoptotic DC that gives viable immature DC the potential to induce Foxp3 1 Treg. Taken together, these findings identify uptake of apoptotic DC by viable immature DC as an immunologically tolerogenic event.Key words: Apoptosis . Autoimmunity . DC . Tolerance Introduction DC are professional antigen-presenting cells, which are well positioned in peripheral tissues to capture foreign antigens. DC are phagocytic and can ingest apoptotic cells, and hence are affected by the death of other cells in close proximity [1][2][3]. Clearance of apoptotic cells results in their removal from tissues, and provides protection from release of pro-inflammatory contents. Necrotic cells impact the immune response by acting as ''danger signals'', whereas apoptotic cells are cleared without an immunological response [3,4]. Studies have identified necrotic cells acting as adjuvants, whereas apoptotic cells have been reported as immunogenic [5][6][7] or immunosuppressive [8,9]. DC apoptosis in itself is an important event for maintenance of tolerance. Defects in DC apoptosis have been linked to the development of autoimmunity with systemic autoimmune diseases modeled in transgenic mice harboring defects in DC apoptosis [10] but not in mice with apoptosis defects in T and B cells [11][12][13]. However, it is unclear how defects in DC apoptosis 1022can trigger autoimmune responses. Furthermore, spontaneous DC apoptosis has been reported in sepsis as well as breast cancer patients with its significance being unclear [14][15][16]. Most patient deaths associated with sepsis occur at later time points and are associated with prolonged immunosuppression [17]. In this later stage, there is marked apoptosis of DC, with no effects on macrophage and neutrophil apoptosis. In addition, immunostimulants such as CpG DNA inhibit DC apoptosis [18], whereas the deficiency of pro-apoptotic Bim protein in DC results in autoimmunity [19].Immature DC have the ability to acquire protein complexes or soluble antigen using many different pathways such as macropinocytosis, endocytosis and even through ingestion of entire cells. Despite the importance of DC apoptosis in the immune response, studies ...

The E26 transformation-specific (ETS) family of transcription factors comprises of 27 and 26 members in humans and mice, respectively, which are known to regulate many different biological processes, including cell proliferation, cell differentiation, embryonic development, neoplasia, hematopoiesis, angiogenesis, and inflammation. The epitheliumspecific ETS transcription factor-1 (ESE-1) is a physiologically important ETS transcription factor, which has been shown to play a role in the pathogenesis of various diseases, and was originally characterized as having an epithelial-restricted expression pattern, thus placing it within the epithelium-specific ETS subfamily. Despite a large body of published work on ETS biology, much remains to be learned about the precise functions of ESE-1 and other epithelium-specific ETS factors in regulating diverse disease processes. Clues as to the specific function of ESE-1 in the setting of various diseases can be obtained from studies aimed at examining the expression of putative target genes regulated by ESE-1. Thus, this review will focus primarily on the various roles of ESE-1 in different pathophysiological processes, including regulation of epithelial cell differentiation during both intestinal development and lung regeneration; regulation of dendritic cell-driven T-cell differentiation during allergic airway inflammation; regulation of mammary gland development and breast cancer; and regulation of the effects of inflammatory stimuli within the setting of synovial joint and vascular inflammation. Understanding the exact mechanisms by which ESE-1 regulates these processes can have important implications for the treatment of a wide range of diseases. KEYWORDS: cancer; development; epithelial cell differentiation; ESE-1; ETS transcription factor; inflammation; regeneration The E26 transformation-specific (ETS) family of transcription factors is characterized by a highly conserved 84-aminoacid DNA-binding domain, known as the ETS domain. 1 Because the first member of the ETS family, the v-ets oncogene, was originally discovered as part of a fusion protein with gag and myb expressed by the E26 avian erythroblastosis-transforming retrovirus and its DNA-binding domain is E26 transformation-specific, this 84-amino-acid DNA-binding domain was named the ETS domain. 1 The ETS domain is usually located within the carboxyl-terminal region of the protein as a winged helix-turn-helix structural motif and mediates binding to sites of purine-rich DNA, commonly containing a core consensus sequence of GGAA/T, within the promoter and enhancer regions of target genes. 2,3 Many ETS transcription factors also contain a pointed domain, which is located within the amino-terminal region and is involved in protein-protein interactions. 2 Approximately 30 members of the ETS transcription factor family have been identified in mammals (ie 27 in humans and 26 in mice), 4 and have been shown to play crucial roles in the regulation of many physiological and pathological processes, such as embryonic develo...

Dendritic cell (DC) apoptosis has been shown to play a role in maintaining a balance between tolerance and immunity. However, the mechanisms of how DC apoptosis affects the immune response are unclear. We have shown that in vitro culture of apoptotic DCs with immature DCs, results in their uptake by immature DCs, which subsequently turn into tolerogenic DCs, which then secrete TGF-β1 and induce Foxp3+ regulatory T cells (Tregs). In this study we looked at the effects of apoptotic DCs in vivo. Here we show that apoptotic DCs are taken up by viable DCs in vivo, which suppresses the ability of viable DCs to undergo maturation and subsequent migration to the lymph nodes in response to LPS. Additionally, delivery of apoptotic DCs to LPS inflamed lungs results in resolution of inflammation, which is mediated by the ability of apoptotic DCs to suppress response of viable DCs to LPS. Additionally, apoptotic DCs also induce TGF-β1 secretion in the mediastinal lymph nodes, which results in expansion of Foxp3+ Tregs. Most importantly, we show that delivery of apoptotic DCs followed by OVA in CFA to mice suppresses T cell response to OVA and instead induces de novo generation of OVA-specific Tregs. Furthermore, delivery of apoptotic DCs followed by OVA in CFA results in expansion of Tregs in TCR transgenic (OT-II) mice. These findings demonstrate that apoptotic DCs are taken up by viable DCs in vivo, which promotes tolerance through suppression of DC maturation and induction of Tregs.

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Elf3 belongs to the Ets family of transcription factors and has been implicated in inflammation. Elf3 is highly expressed in the lungs, and Elf3−/− mice are impaired in IL-6 production after intranasal LPS exposure. To identify the role of Elf3 in Th17-driven pulmonary inflammation, we have performed epicutaneous sensitization of Elf3−/− mice with OVA followed by airway OVA challenge and have identified Elf3−/− mice to be impaired in induction of Th17 response, attributable to impairment of IL-6 production by dendritic cells (DCs). However, increased serum levels of OVA-specific IgG1 and IgE were observed, pointing toward an exaggerated Th2 response. To study Th2 response, we performed i.p. sensitization of Elf3−/− mice with OVA and confirmed loss of Elf3 to result in an aggravated Th2 response, characterized by increased generation of IL-4–producing T cells, increased levels of OVA-specific IgE and IgG1 Ab titers, and increased serum levels of Th2 cytokines, together with extensive inflammation and mucus production in airways. Elf3−/− DCs were impaired in priming Th1 differentiation, which, in turn, promoted Th2 differentiation. This was mediated by the ability of Elf3−/− DCs to undergo hypermaturation but secrete significantly lower levels of IL-12 in response to inflammatory stimuli. The impairment of IL-12 production was due to impairment of IL-12p40 gene induction in Elf3−/− DCs in response to inflammatory stimuli. Taken together, our study identifies a novel function of Elf3 in regulating allergic airway inflammation by regulating DC-driven Th1, Th2, and Th17 differentiation.

Adenoviral vector-mediated gene delivery has been vastly investigated for cystic fibrosis (CF) gene therapy; however, one of its drawbacks is the low efficiency of gene transfer, which is due to basolateral colocalization of viral receptors, immune responses to viral vectors and the presence of a thick mucus layer in the airways of CF patients. Therefore, enhancement of gene transfer can lead to reduction in the viral dosage, which could further reduce the acute toxicity associated with the use of adenoviral vectors. Nacystelyn (NAL) is a mucolytic agent with anti-inflammatory and antioxidant properties, and has been used clinically in CF patients to reduce mucus viscosity in the airways. In this study, we show that pretreatment of the airways with NAL followed by administration of adenoviral vectors in complex with DEAE-Dextran can significantly enhance gene delivery to the airways of mice without any harmful effects. Moreover, NAL pretreatment can reduce the airway inflammation, which is normally observed after delivery of adenoviral particles. Taken together, these results indicate that NAL pretreatment followed by adenoviral vector-mediated gene delivery can be beneficial to CF patients by increasing the efficiency of gene transfer to the airways, and reducing the acute toxicity associated with the administration of adenoviral vectors.

These findings show that there are clear gender differences in naphthalene-induced lung injury and repair.

Although the translocation of metallothionein (MT) from cytoplasm to nucleus has been demonstrated in liver during times of high requirement for zinc (fetal development and the neonatal period), the role of MT in cellular growth is not well understood. In this study, a potential role of MT in liver regeneration was investigated in wild type (WT) and MT-I and MT-II gene knockout (MT-null) mice after 35% partial hepatectomy (PH) or sham laparotomy. Hepatic MT levels and proliferation index were measured at 0, 5, 15, 24, 36, 48, and 60 hrs after PH and 48 hrs after sham laparotomy (control). MT levels were increased in WT mice (peak at 24 hrs after PH) and declined to normal levels by 60 hrs after PH. Immunohistochemical staining for MT in WT mice indicated the presence of MT in both nucleus and cytoplasm of hepatocytes at 24 hrs after PH, whereas MT was present mainly in the cytoplasm at 36-60 hrs after PH and 48 hrs after sham laparotomy. Hepatic proliferation index in both WT and MT-null mice, as determined by argyrophilic nucleolar organizing region staining and proliferating cell nuclear antigen immunohistochemical staining, reached a peak at 48 hrs and declined by 60 hrs after PH. Cell proliferation was significantly less in MT-null mice as compared to WT mice during liver regeneration after PH. These results suggest that MT may play a positive role in hepatic regeneration after PH.