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Epstein-Barr virus-induced gene 3 (EBI3) is a subunit commonto IL-27, IL-35, and IL-39. Here, we explore an intracellular role of EBI3 that is independent of its function In cytokines. EBI3-deflclent naive [CD4.sup.+] T cells had reduced IFN-[gamma] production and failed to induce T cell-dependent colitis in mice. Similarly reduced IFN-[gamma] production was observed In vitro in EBI3-deficient [CD4.sup.+] T cells differentiated under pathogenic Th17 polarizing conditions with IL-23. This is because the induction of expression of one of the IL-23 receptor (IL-23R) subunits, IL-23R[alpha], but not another IL-23R subunit, IL-12R[beta]1, was selectively decreased at the protein level, but not the mRNA level. EBI3 augmented IL-23R[alpha] expression via bindingto the chaperone molecule calnexin and to IL-23R[alpha] in a peptide-dependent manner, but not a glycan-dependent manner. Indeed, EBI3 failed to augment IL-23R[alpha] expression in the absence of endogenous calnexin. Moreover, EBI3 poorly augmented the expression of C149R, an IL-23R[alpha] variant that protects against the development of human colitis, because binding of EBI3 to the variant was reduced. Taken together with the result that EBI3 expression Is Inducible InT cells, the present results suggest that EBI3 plays a critical role in augmenting IL-23R[alpha] protein expression via calnexin under inflammatory conditions., Introduction Cytokines of the IL-12 family play critical roles in regulating the differentiation of Th cells and their effector functions (1). These cytokines are composed of 2 distinct subunits forming [...]

Acute liver failure (ALF) is a life-threatening condition, and liver transplantation is the only therapeutic option. Although immune dysregulation is central to its pathogenesis, the precise mechanism remains unclear. Here, we show that the number of peripheral and hepatic plasmacytoid DCs (pDCs) decrease during acute liver injury in both humans and mice. Selective depletion of pDCs in [Siglech.sup.dtr/+] mice exacerbated concanavalin A-induced acute liver injury. In contrast, adoptively transferred BM-derived pDCs preferentially accumulated in the inflamed liver and protected against liver injury. This protective effect was independent of TLR7 and TLR9 signaling, since a similar effect occurred following transfer of MyD88-deficient pDCs. Alternatively, we found an unexpected immunosuppressive role of pDCs in an IL-35-dependent manner. Both Il12a and Ebi3, heterodimeric components of IL-35, were highly expressed in transferred pDCs and [CD4.sup.+][CD25.sup.+] Tregs. However, the protective effect of pDC transfer was completely lost in mice depleted of Tregs by anti-CD25 antibody. Moreover, pDCs derived from IL-35-deficient mice had less of a protective effect both in vivo and in vitro even in the presence of Tregs. These results highlight a unique aspect of pDCs in association with Tregs, serving as a guide for immunotherapeutic options in ALF., Introduction Acute liver failure (ALF) is a life-threatening condition characterized by progressive and extensive multilobular damage of the hepatocytes and massive intrahepatic infiltration of immune cells. However, there are no [...]

The current success of mRNA vaccines against COVID‐19 has highlighted the effectiveness of mRNA and DNA vaccinations. Recently, we demonstrated that a novel needle‐free pyro‐drive jet injector (PJI) effectively delivers plasmid DNA into the skin, resulting in protein expression higher than that achieved with a needle syringe. Here, we used ovalbumin (OVA) as a model antigen to investigate the potential of the PJI for vaccination against cancers. Intradermal injection of OVA‐expression plasmid DNA into mice using the PJI, but not a needle syringe, rapidly and greatly augmented OVA‐specific CD8+ T‐cell expansion in lymph node cells. Increased mRNA expression of both interferon‐γ and interleukin‐4 and an enhanced proliferative response of OVA‐specific CD8+ T cells, with fewer CD4+ T cells, were also observed. OVA‐specific in vivo killing of the target cells and OVA‐specific antibody production of both the IgG2a and IgG1 antibody subclasses were greatly augmented. Intradermal injection of OVA‐expression plasmid DNA using the PJI showed stronger prophylactic and therapeutic effects against the progression of transplantable OVA‐expressing E.G7‐OVA tumor cells. Even compared with the most frequently used adjuvants, complete Freund's adjuvant and aluminum hydroxide with OVA protein, intradermal injection of OVA‐expression plasmid DNA using the PJI showed a stronger CTL‐dependent prophylactic effect. These results suggest that the novel needle‐free PJI is a promising tool for DNA vaccination, inducing both a prophylactic and a therapeutic effect against cancers, because of prompt and strong generation of OVA‐specific CTLs and subsequently enhanced production of both the IgG2a and IgG1 antibody subclasses. [ABSTRACT FROM AUTHOR]

To clarify the effect of collagen addition to transplanted adipose tissue on angiogenesis, cell proliferation and tissue remodelling process and reveal whether collagen addition contributes to improving transplanted adipose tissue engraftment in rats. Adipose tissue was harvested from the inguinal and injected into the back of the rat, in addition to collagen. Engraftment tissue was harvested, semi‐quantitatively evaluated and underwent haematoxylin and eosin or Perilipin staining. Moreover, we evaluated viable adipocyte counts and neovascularisation. Macrophages were evaluated using flow cytometry, and the adiponectin or vascular endothelial growth factor (VEGF) mRNA was detected using real‐time polymerase chain reaction. By collagen addition to transplanted adipose tissue, higher engraftment rate semi‐quantitatively and a greater number of new blood vessels histologically were identified. Perilipin staining revealed a higher adipocyte number. The total cell, M1 macrophage and M2 macrophage count were higher. There was increased adiponectin mRNA significantly at week 4 compared to that at week 1 after transplantation. Note that the expression levels of VEGF mRNA increased. In rats, adding collagen enhanced cell proliferation, induced M2 macrophages, which are involved in wound healing, and promoted adipocytes and neovascularisation. Therefore, collagen addition to transplanted adipose tissue could increase the engraftment rate of adipose tissue. [ABSTRACT FROM AUTHOR]

Intestinal adhesions are bands of fibrous tissue that connect the loops of the intestine to each other, to other abdominal organs or to the abdominal wall (1-3). Fibrous tissue formation is regulated by the balance between plasminogen activator inhibitor type 1 (PAI-1) and tissue-type plasminogen activator (tPA), which reciprocally regulate fibrin deposition. Several components of the inflammatory system, including cytokines (4), chemokines, cell adhesion molecules and neuropeptide substance P, have been reported to participate in adhesion formation (4-7) We have used cecal cauterization to develop a unique experimental mouse model of intestinal adhesion. Mice developed severe intestinal adhesion after this treatment. Adhesion development depended upon the interferon-[gamma] (IFN-[gamma]) and signal transducer and activator of transcription-1 (STATU system. Natural killer T (NKT) cell-deficient mice developed adhesion poorly, whereas they developed severe adhesion after reconstitution with NKT cells from wild-type mice, suggesting that NKT cell IFN-[gamma] production is indispensable for adhesion formation. This response does not depend on STAT4, STATE, interleukin-12 (IL-12), IL-18, tumor necrosis factor-[alpha], Toll-like receptor 4 or myeloid differentiation factor-88-mediated signals. Wild-type mice increased the ratio of PAI-1 to tPA after cecal cauterization, whereas [Ifng.sup.-/-] or Stat[1-/-] mice did not, suggesting that IFN-[gamma] has a crucial role in the differential regulation of PAI-1 and tPA. Additionally, hepatocyte growth factor, a potent mitogenic factor for hepatocytes (8,9), strongly inhibited intestinal adhesion by diminishing IFN-[gamma] production, providing a potential new way to prevent postoperative adhesions., Abdominal adhesion formation occurs in 67-93% of abdominal surgeries [10-13]. Adhesion also develops after abdominal bacterial infections, such as peritonitis [14]. A recent study has indicated that T helper type [...]