Tetsuo Tsuchida

The Ubiquitin Ligase TRIM56 Regulates Innate Immune Responses to Intracellular Double-Stranded DNA

The innate immune system detects pathogen- and host-derived double-stranded DNA exposed to the cytosol and induces type I interferon (IFN) and other cytokines. Here, we identified interferon-inducible tripartite-motif (TRIM) 56 as a regulator of double-stranded DNA-mediated type I interferon induction. TRIM56 overexpression enhanced IFN-β promoter activation after double-stranded DNA stimulation whereas TRIM56 knockdown abrogated it. TRIM56 interacted with STING and targeted it for lysine 63-linked ubiquitination. This modification induced STING dimerization, which was a prerequisite for recruitment of the antiviral kinase TBK1 and subsequent induction of IFN-β. Taken together, these results indicate that TRIM56 is an interferon-inducible E3 ubiquitin ligase that modulates STING to confer double-stranded DNA-mediated innate immune responses.

Involvement of the NLRP3 Inflammasome in Innate and Humoral Adaptive Immune Responses to Fungal β-Glucan

Fungal β-glucan, such as curdlan, triggers antifungal innate immune responses as well as shaping adaptive immune responses. In this study, we identified a key pathway that couples curdlan to immune responses. Curdlan promoted the production of the proinflammatory cytokine IL-1β by dendritic cells and macrophages through the NLRP3 inflammasome. Stimulation with Candida albicans and Saccharomyces cerevisiae also triggered the NLRP3 inflammasome-mediated IL-1β production. In vivo, NLRP3 was required for efficient Ag-specific Ab production when curdlan was used as an adjuvant, whereas it was dispensable for the induction of Th1 and Th17 cell differentiation. Furthermore, stimulation of purified B cells with curdlan-induced CD69 up-regulation and IgM production while stimulation with other NLRP3 inflammasome activators, such as silica and aluminum salt, did not. Notably, this induction required NLRP3 but was independent of Toll-like receptor and IL-1 receptor family signaling, suggesting the presence of NLRP3-dependent and IL-1 receptor family independent mechanisms in B cells responsible for Ab responses. Collectively, these findings reveal a critical role for the NLRP3 inflammasome in the regulation of antifungal innate immune responses as well as B cell activation.

Properties of cis- and trans-bis(crown ether)s for complexation and extraction of alkali metal picrates.

The properties of cis- and trans-bis(crown ether)s containing benzo-15-crown-5 or benzo-18-crown-6 units as complexants and extractants for alkali metal picrates have been studied. The optical spectra suggest that the cis-bis(crown ether)s can form intramolecular 2:1 crown ether unit/cation complexes with particular metal cations easily, while the trans-bis(crown ether)s can form only 1:1 crown ether unit/cation complexes because of the unfavourable trans configuration for the formation of the 2:1 complexes. It was found that the cis isomer possesses much higher extractive power than the trans isomer for the metal cations, which also reflects their complexing properties. The extraction equilibrium constants and thermodynamic quantities have been also evaluated, and the effect of the stereochemical structure of the bis(crown ether) on the complexing and extractive properties is discussed.

Suppressive Effect of Ultraviolet-B-Irradiation of Epidermal Cells on the Induction of Contact Sensitivity

Contact sensitivity to trinitrophenyl (TNP) hapten was induced by subcutaneous (s.c.) administration of TNP‐modified syngeneic spleen cells or epidermal cells (EC) (TNP‐EC). Intraperitoneal (i.p.) inoculation of TNP‐EC resulted in a comparable response, whereas i.p. administration of TNP‐spleen cells or TNP‐modified‐ultraviolet (UV)‐preirradiated EC (TNP‐UV‐EC) failed to induce TNP‐contact sensitivity responses. The present study investigates the effect of UV‐irradiation on the potential of EC for inducing the contact sensitivity response. Exposure of BALB/c mouse EC in vitro to 1600 J/m2 of UV‐B before they were modified with TNP had no discernible effect on the Ia‐positivity and viability of EC. Coexistence of TNP‐UV‐EC had no inhibitory effect upon the contact sensitivity response induced by TNP‐EC via the i.p. route. The absence of suppressor cell generation was substantiated by the adoptive transfer of spleen cells from mice administered TNP‐UV‐EC i.p. to normal syngeneic mice. The effect of interleukin 1 (IL‐1) or epidermal cell‐derived thymocyte‐activating factor (ETAF) in restoring the ability of TNP‐UV‐EC to induce contact sensitivity was examined. IL‐1 or ETAF administered along with TNP‐spleen cells i.p. induced a potent contact sensitivity response, whereas the same preparations of IL‐1 or ETAF were unable to restore the contact sensitivity induction by TNP‐UV‐EC. The results are discussed in the context of UV‐induced cell surface changes of the Langerhans cell population.