Shizuo Akira

Bio: Shizuo Akira is an academic researcher from Osaka University. The author has contributed to research in topics: Innate immune system & Immune system. The author has an hindex of 261, co-authored 1308 publications receiving 320561 citations. Previous affiliations of Shizuo Akira include University of California, Berkeley & Wakayama Medical University.

Induction of an anti-inflammatory cytokine, IL-10, in dendritic cells after toll-like receptor signaling

Abstract: Interleukin-10 (IL-10) is an anti-inflammatory cytokine that modulates innate and adaptive immunity. IL-10 transcripts and the protein were induced in murine bone marrow-derived dendritic cells (BMDCs) after toll-like receptor (TLR) stimulation. IL-10 induction was TLR ligand selective, in that CpG DNA, imidazoquinolin, peptidoglycan, and zymosan but not lipopolysaccharide (LPS) and poly I:C led to IL-10 production. IL-10 induction was, however, completely absent in MyD88(/) DCs that lacked a TLR adaptor showing that IL-10 induction depends on TLR signaling. Kinetic analysis of IL-10 induction by CpG and imidazoquinolin revealed a prolonged lag phase prior to a measurable rise in transcript levels, which peaked at 12-24 h after stimulation. Stat3, implicated in IL-10 gene transcription, was also induced after TLR stimulation with the kinetics similar to those of IL-10 induction. Further, Stat3 was phosphorylated and bound to the IL-10 promoter in TLR-stimulated DCs. Supporting a link with IL-10 induction, STAT3 induction was absent in MyD88(/) DCs. These data suggest a two-step model where the initial TLR signaling induced proinflammatory cytokines, which then activated Stat3, leading to the induction of IL-10. TLR-stimulated IL-10 production may regulate DC maturation steps, thereby influencing the ensuing immune responses.

Involvement of Toll-Like Receptor 4 Signaling in Interferon-γ Production and Antitumor Effect by Streptococcal Agent OK-432

Abstract: Background: The streptococcal agent OK-432 has been used for immunotherapy of head and neck cancer, among other malignancies, but its mechanism of action is unknown. Because the Toll-like receptor 4 (TLR4)/MD-2 complex is important in enabling the mammalian immune system to recognize bacterial components, we investigated whether expression of the TLR4 and MD-2 genes is associated with OK-432-induced anticancer immunity. Methods: Peripheral blood mononuclear cells (PBMCs) from 28 patients with head and neck cancer were analyzed for TLR4 and MD-2 mRNA expression by reverse transcription–polymerase chain reaction (RT–PCR) analysis. PBMCs were treated in vitro with OK-432 or with OK-PSA (a lipoteichoic-acidrelated molecule that is an active component of OK-432), and interferon-gamma (IFN-) mRNA expression, an immune response measure, was analyzed by RT–PCR. Patient sera collected 24 hours after OK-432 administration were examined for IFN- protein using an enzyme-linked immunosorbent assay. Lewis lung carcinoma-bearing wild-type C57BL/6 and TLR4-deficient mice (four mice per group) received intraperitoneal injections of OK-432, and tumor volumes and sera IFN- levels were measured over time. All statistical tests were two-sided. Results: Twenty patients expressed both TLR4 and MD-2. Expression of TLR4 and MD-2 genes was associated with the in vivo IFN- induction in 19 patients administered OK-432 (Fisher’s exact test P<.001). Although both OK-432 and OK-PSA induced IFN- expression from PBMCs in vitro, expression of TLR4 and MD-2 was associated only with IFN- expression induced by OK-PSA (P<.001). In vivo intraperitoneal administration of OK-432 resulted in an increase of IFN- in sera from wild-type mice but not in sera from TLR4-deficient mice. Tumors in wild-type mice treated with OK-432 were statistically significantly smaller than those in mice treated with saline (P = .007). By contrast, in TLR4-deficient mice, there was no difference in tumor volume between the two treatment groups. Conclusions: TLR4 and MD-2 may mediate OK-432-induced anticancer immunity. [J Natl Cancer Inst 2003;95:316–26]

Plasmacytoid Dendritic Cells Promote Host Defense against Acute Pneumovirus Infection via the TLR7–MyD88-Dependent Signaling Pathway

Abstract: Human respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection in infants. In human infants, plasmacytoid dendritic cells (pDC) are recruited to the nasal compartment during infection and initiate host defense through the secretion of type I IFN, IL-12, and IL-6. However, RSV-infected pDC are refractory to TLR7-mediated activation. In this study, we used the rodent-specific pathogen, pneumonia virus of mice (PVM), to determine the contribution of pDC and TLR7 signaling to the development of the innate inflammatory and early adaptive immune response. In wild-type, but not TLR7- or MyD88-deficient mice, PVM inoculation led to a marked infiltration of pDC and increased expression of type I, II, and III IFNs. The delayed induction of IFNs in the absence of TLR7 or MyD88 was associated with a diminished innate inflammatory response and augmented virus recovery from lung tissue. In the absence of TLR7, PVM-specific CD8 + T cell cytokine production was abrogated. The adoptive transfer of TLR7-sufficient, but not TLR7-deficient pDC to TLR7 gene-deleted mice recapitulated the antiviral responses observed in wild-type mice and promoted virus clearance. In summary, TLR7-mediated signaling by pDC is required for appropriate innate responses to acute pneumovirus infection. It is conceivable that as-yet–unidentified defects in the TLR7 signaling pathway may be associated with elevated levels of RSV-associated morbidity and mortality among otherwise healthy human infants.

Akirin2 is critical for inducing inflammatory genes by bridging IκB-ζ and the SWI/SNF complex.

Abstract: Transcription of inflammatory genes in innate immune cells is coordinately regulated by transcription factors, including NF-κB, and chromatin modifiers. However, it remains unclear how microbial sensing initiates chromatin remodeling. Here, we show that Akirin2, an evolutionarily conserved nuclear protein, bridges NF-κB and the chromatin remodeling SWI/SNF complex by interacting with BRG1-Associated Factor 60 (BAF60) proteins as well as IκB-ζ, which forms a complex with the NF-κB p50 subunit. These interactions are essential for Toll-like receptor-, RIG-I-, and Listeria-mediated expression of proinflammatory genes including Il6 and Il12b in macrophages. Consistently, effective clearance of Listeria infection required Akirin2. Furthermore, Akirin2 and IκB-ζ recruitment to the Il6 promoter depend upon the presence of IκB-ζ and Akirin2, respectively, for regulation of chromatin remodeling. BAF60 proteins were also essential for the induction of Il6 in response to LPS stimulation. Collectively, the IκB-ζ–Akirin2–BAF60 complex physically links the NF-κB and SWI/SNF complexes in innate immune cell activation. By recruiting SWI/SNF chromatin remodellers to IκB-ζ, transcriptional coactivator for NF-κB, the conserved nuclear protein Akirin2 stimulates pro-inflammatory gene promoters in mouse macrophages during innate immune responses to viral or bacterial infection.

Molecular and cellular mechanisms of DNA vaccines.

Abstract: Although DNA vaccines are already in use for treatment of some animal diseases, they suffer from lower immunogenicity in humans which limits their effectiveness. Thus, recent studies have been focused on strategies to improve the immunogenicity of DNA vaccines. However, there is little known about the molecular and immunological mechanisms by which DNA vaccines work. It has long been the central dogma that DNA vaccine immunogenicity can be attributed to its immunostimulatory CpG motifs acting as 'a built-in adjuvant", which is recognized by Toll-like receptor (TLR) 9, the sole receptor for CpG motifs. Recent research, however, has provided evidence for a new mechanism of action for DNA vaccines. It was reported that the adjuvant effect of plasmid DNA is mediated by its double-stranded structure, which activates TBK1-dependent innate immune signaling pathways in the absence of TLRs. Moreover, TBK1-signaling may delineate direct or indirect (cross) antigen presentation through distinct types of cells in vivo, critical for the induction of antigen-specific CD4(+) or CD8(+) T cells, respectively. This additional information about the mechanism of action of DNA vaccines will lead to improvements in their efficacy and safety.

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine.

Abstract: Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the resulting coronavirus disease 2019 (Covid-19) have afflicted tens of millions of people in a world...

Cancer-related inflammation.

Abstract: The mediators and cellular effectors of inflammation are important constituents of the local environment of tumours. In some types of cancer, inflammatory conditions are present before a malignant change occurs. Conversely, in other types of cancer, an oncogenic change induces an inflammatory microenvironment that promotes the development of tumours. Regardless of its origin, 'smouldering' inflammation in the tumour microenvironment has many tumour-promoting effects. It aids in the proliferation and survival of malignant cells, promotes angiogenesis and metastasis, subverts adaptive immune responses, and alters responses to hormones and chemotherapeutic agents. The molecular pathways of this cancer-related inflammation are now being unravelled, resulting in the identification of new target molecules that could lead to improved diagnosis and treatment.