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Abstract A close causal relationship has been suggested to exist between cancer and periodontitis. We hypothesized that the immune surveillance system is impaired in patients with periodontitis, which contributes to cancer development and growth. Therefore, the present study investigated the relationship between immune surveillance mechanisms and periodontitis in cancer patients. The presence or absence of periodontitis was assessed and the peripheral blood (PB) concentrations of IL-6, immunosuppressive cytokines (VEGF, TGF-β1, and CCL22) and proportion of T regulatory cells (Treg, CD3 + CD4 + CD25 + Foxp3 +) were measured. Subjects were classified into the following four groups: non-cancer patients without periodontitis (C − P −), non-cancer patients with periodontitis (C − P +), cancer patients without periodontitis (C + P −), and cancer patients with periodontitis (C + P +). The results of a multivariate analysis showed that the PB concentration of IL-6 was significantly higher in C + than in C- and higher in C + P + than in C + P −. The PB proportion of Treg was significantly higher in C + P + than in C + P −, C − P + , and C − P −. The results of this study suggested that the presence of periodontitis and cancer synergistically increased Treg in PB, which may be one of the underlying causes of immunosuppression and immune evasion in cancer. It was also suggested that the presence of periodontal disease and/or cancer also increases IL-6 in PB, which would be associated with cancer progression. These results suggest the possibility that the presence of periodontitis might synergistically contribute to cancer progression.

Nonvesicular extracellular RNA (nex-RNA) that are not packed in extracellular vesicles is detected outside the cell, but it is poorly understood. Here the authors report that nex-RNA is captured by a zinc finger protein and transported to the nucleus to enhance antimetastatic characters of the cell.

The kinase TAK is required for the development of conventional and regulatory T cells. We previously reported that mice with conditional deletion of TAK1 in T cells (Lck-cre:TAK1fl/fl mice) exhibited severe T lymphopenia, and were nevertheless predisposed to spontaneous colitis with unknown etiology. Here we focused on the immunopathological mechanism in colitic Lck-cre:TAK1fl/fl mice. We found that 'leaky' CD4+ T cells retaining TAK1 acquired inflammatory phenotypes that contribute to disease onset in Lck-cre:TAK1fl/fl mice. Furthermore, the gut microbiota-triggered signaling was also a key event leading to the pathogenesis. We discovered that Lck-cre:TAK1fl/fl mice were almost completely devoid of TCRαβ+CD8α+ intestinal intraepithelial lymphocytes (IELs) and this was largely due to the developmental defect of the thymic precursors by TAK1 deficiency. Remarkably, transfer of TCRαβ+CD8α+ IELs from wild-type mice ameliorated colitis in Lck-cre:TAK1fl/fl mice. Taken together, our current study highlighted the emerging role of TAK1 in configuring the gut-specialized T cell subset, which regulates mucosal homeostasis under lymphopenic conditions.

White blood cell (WBC) count will greatly facilitate the timely diagnosis and management of health conditions of dairy cattle, including clinical mastitis. We propose a WBC counting device for dairy cattle using a microchannel with field-flow fractionation incorporating light scattering, which allows both the separation and counting of WBCs. The performance characteristics of the microchannel were optimized to separate particles by size through three-dimensional (3D) numerical simulations. The fabricated microchannel was evaluated using three mock beads with sizes of 3.5 pm representing milk fat globules (MFGs), 10 pm for WBCs, and 30 pm for cancer cells. The pinched flow microfluidic device was useful for separating particles with diameters of 10 and 30 pm. The WBC count was determined using the fabricated WBC counting device. Light scattering was effective for separating cells of 10 pm diameter or less such as MFGs and WBCs that pass through a close streamline. The linear regression analysis of the calibration curve for the WBC counting device showed a multiple determination coefficient of 0.98. The performance of our WBC counting device approached that of laboratory-based tests, allowing the quantitative and rapid analysis of the concentration of WBCs in raw bovine milk in field applications. [ABSTRACT FROM AUTHOR]

TGF-β-activated kinase 1 (TAK1) is known to play vital roles for innate and adaptive immunity; however, little is known about its potential role in limiting biological responses such as inflammation. In this study, we report that macrophage TAK1 participates in negatively regulating inflammation by restraining proinflammatory cell death. Macrophages from TAK1-deficient mice underwent cell death in response to LPS and poly(I:C), which took place in a manner dependent on TLR/TRIF-induced active Caspase8-mediated cleavage of gasdermin D, known as an executioner of pyroptosis. Likewise, TNF-α induced Caspase8-dependent gasdermin D processing following cell death in TAK1-deficient macrophages. Importantly, we demonstrated that this type of proinflammatory macrophage death is linked to susceptibility to septic shock in mice lacking TAK1 in macrophages in a TNF-α-independent fashion. Taken together, our data revealed that TAK1 acts as a signaling checkpoint to protect macrophages from unique proinflammatory cell death, ensuring the maintenance of innate immune homeostasis. [ABSTRACT FROM AUTHOR]

The traditional Japanese health care custom recommends that a suitable volume of water is consumed. However, physiological and immunological mechanisms in support of this practice are unknown. Therefore, we conducted rat and rabbit in vivo experiments to investigate the effects of intragastric administration of distilled water on the jejunal-originated lymph flow and the concentrations and total flux of cells, albumin, long-chain fatty acids, and innate lymphoid cell 3 (ILC-3)-secreted interleukin-22 (IL-22) through mesenteric lymph vessels. The distribution and activity of ILC-3 in rat small intestine by water intake were evaluated using flow cytometry and RT-PCR. The intragastric administration of distilled water caused significant increases in rat mesenteric lymph flow and in the total flux of cells, albumin, long-chain fatty acids, and IL-22 through the lymph vessels. Intravenously injected Evans blue dye was rapidly transported into rabbit mesenteric lymph vessel and cisterna chyli. The distribution of ILC-3 and the expression of IL-22 mRNA were maximal in the lamina propria cells of the rat jejunum. No significant presence of ILC-3 in the lymph was observed in the control and under water intake conditions. In conclusion, the absorbed water in the jejunum is transported through mesenteric lymph vessels. The higher permeability of albumin in the jejunal microcirculation may play key roles in the transport of consumed water and the reservoir and transporter of long-chain fatty acids. Water intake also accelerates the transfer of IL-22 to the mesenteric lymph, which may contribute, in part, to maintaining and promoting the innate immunity in the body. [ABSTRACT FROM AUTHOR]

Transforming growth factor (TGF)-β-activating kinase 1 (TAK1) is critical for Toll-like receptor- and tumor necrosis factor-mediated cellular responses. In B cells, TAK1 is essential for the activation of mitogen-activated protein kinases (MAPKs), but not nuclear factor-κB (NF-κB), in antigen receptor signaling. In this study, we generate T cell-specific TAK1-deficient (LckCre/+Tak1flox/flox) mice and show that TAK1 is indispensable for the maintenance of peripheral CD4 and CD8 T cells. In thymocytes, TAK1 is essential for TCR-mediated activation of both NF-κB and MAPKs. Additionally, LckCre/+Tak1flox/flox mice developed colitis as they aged. In these mice, accumulations of activated/memory T cells as well as B cells were observed. Development of regulatory T (Treg) cells in thymus was abrogated in LckCre/+Tak1flox/flox mice, suggesting that the loss of Treg cells is the cause of the disease. Together, the results show that TAK1, by controlling the generation of central Treg cells, is important for preventing spontaneously developing colitis. [ABSTRACT FROM AUTHOR]

Polyubiquitination of proteins plays a critical role in the activation of immune cells. K63-linked polyubiquitin-binding proteins TGF-β-activated kinase 1 (TAK1)-binding protein (TAB)2 and TAB3 are implicated in NF-κB signaling via TAK1 activation. However, TAB2 alone is dispensable for NF-κB activation in embryonic fibroblasts, and the functional roles of TAB2 and TAB3 in immune cells has yet to be clarified. In this study, we demonstrate that TAB2 and TAB3 are essential for B cell activation leading to Ag-specific Ab responses, as well as B-1 and marginal zone B cell development. TAB2 and TAB3 are critical for the activation of MAPKs, especially ERK, but not NF-κB, in response to TLR and CD40 stimulation in B cells. Surprisingly, TAB2 and TAB3 are dispensable for TAK1 activation in B cells, indicating that TAB2 and TAB3 activate MAPKs via a pathway independent of TAK1. In contrast to B cells, macrophages lacking TAB2 and TAB3 did not show any defects in the cytokine production and the signaling pathway in response to TLR stimulation. Furthermore, TAB2 and TAB3 were dispensable for TNF-induced cytokine production in embryonic fibroblasts. Thus, TAB2- and TAB3-mediated K63-linked polyubiquitin recognition controls B cell activation via MAPKs, but not the TAK1/NF-κB axis. [ABSTRACT FROM AUTHOR]

NK cell receptors (NKRs) such as NK1.1, NKG2D, and Ly49s are expressed on subsets of CDld-independent memory phenotype CD8+ and CD4-CD8- T cells. However, the mechanism for the generation and functions of these NKR+ T cells remained elusive. In this study, we found that CDld-independent Ly49+ T cells were reduced severely in the spleen, bone marrow, and liver, but not thymus, in mice doubly deficient for IFN regulatory factor-2 (IRF-2) and CD Id, in which the overall memory phenotype T cell population was contrastingly enlarged. Because a large fraction of Ly49+ T cells coexpressed NK1.1 or NKG2D, the reduction of Ly49+ T cells resulted indirectly in underrepresentation of NK1.1+ or NKG2D+ cells. Ly49+ T cell deficiency was observed in IRF-2-/- mice additionally lacking IFN-α/βR a-chain (IFNARl) as severely as in IRF-2-/- mice, arguing against the involvement of the accelerated IFN-α/β signals due to IRF-2 deficiency. Rather, mice lacking IFN-α/βR alone also exhibited relatively milder Ly49+ T cell reduction, and IL-2 could expand Ly49+ T cells from IFNARl-/-, but not from IRF-2-/-, spleen cells in vitro. These results together indicated that IRF-2 acted in Ly49+ T cell development in a manner distinct from that of IFN-α/β signals. The influence of IRF-2 deficiency on Ly49+ memory phenotype T cells observed in this study suggested a unique transcriptional program for this T cell population among other NKR+ T and memory phenotype T cells. [ABSTRACT FROM AUTHOR]

The human homologue of Drosophila Toll (hToll), also called Toll-like receptor 4 (TLR4), is a recently cloned receptor of the IL-I/Toll receptor family. Interestingly, the TLR4 gene has been localized to the same region to which the Lps locus (endotoxin unresponsive gene locus) is mapped. To examine the role of TLR4 in LPS responsiveness, we have generated mice lacking TLR4. Macrophages and B cells from TLR4-deficient mice did not respond to LPS. All these manifestations were quite similar to those of LPS-hyporesponsive C3H/HeJ mice. Furthermore, C3H/HeJ mice have, in the cytoplasmic portion of TLR4, a single point mutation of the amino acid that is highly conserved among the IL-l/Toll receptor family. Overexpression of wild-type TLR4 but not the mutant TLR4 from C3H/HeJ mice activated NF-κB. Taken together, the present study demonstrates that TLR4 is the gene product that regulates LPS response. [ABSTRACT FROM AUTHOR]

A switchlike response in nuclear factor-κB (NF-κB) activity implies the existence of a threshold in the NF-κB signaling module. We show that the CARD-containing WIAGUK protein 1 (CARMA1, also called CARD1D-TAK1 (MAP3K7)-inhibitor of NF-κB (IκB) kinase-β (IKKβ) module is a switch mechanism for NF-βB activation in B cell receptor (BCR) signaling. Experimental and mathematical modeling analyses showed that IKK activity is regulated by positive feedback from IKKβ to TAK1, generating a steep dose response to BCR stimulation. Mutation of the scaffolding protein CARMA1 at serine-578, an IKKβ target, abrogated not only late TAK1 activity, but also the switchlike activation of NF-κB in single cells, suggesting that phosphorylation of this residue accounts for the feedback. [ABSTRACT FROM AUTHOR]