Showing papers by "Shizuo Akira published in 1998"
TL;DR: It is demonstrated that MyD88 is a critical component in the signaling cascade that is mediated by IL-1 receptor as well as IL-18 receptor, and increases in interferon-gamma production and natural killer cell activity in response to IL- 18 are abrogated.
2,063 citations
TL;DR: The in vivo role of IL-18 and IL-12 in NK activity, as well as in in vivo Th1 response is demonstrated, demonstrating the important role of both IL- 18 andIL-12 as cytokine secreted from activated macrophages and induces IFNgamma production.
911 citations
Journal Article•
TL;DR: It is shown that IL-12 and IL-18 promptly and synergistically induce T and B cells to develop into IFN-gamma-producing cells without engaging their Ag receptors and the mechanism underlying differences inIL-18 responsiveness between Th1 and Th2 cells is studied.
Abstract: IL-18 is a product of macrophages and with IL-12 strikingly induces IFN-gamma production from T, B, and NK cells. Furthermore, IL-18 and 1L-12 synergize for IFN-gamma production from Th1 cells, although this combination fails to affect Th2 cells. In this study, we show that IL-12 and IL-18 promptly and synergistically induce T and B cells to develop into IFN-gamma-producing cells without engaging their Ag receptors. We also studied the mechanism underlying differences in IL-18 responsiveness between Th1 and Th2 cells. Pretreatment of T or B cells with IL-12 rendered them responsive to IL-18, which induces cell proliferation and IFN-gamma production. These IL-12-stimulated cells had both high and low affinity IL-18R and an increased IL-18R mRNA expression. In particular, IL-12-stimulated T cells strongly and continuously expressed IL-18R mRNA. However, when T cells developed into Th1 cells after stimulation with anti-CD3 and IL-12, they lowered this IL-12-induced-IL-18R mRNA expression. Then, such T cells showed a dominant response to anti-CD3 by IFN-gamma production when they were subsequently stimulated with anti-CD3 and IL-18. In contrast, Th2 cells did not express IL-18R mRNA and failed to produce IFN-gamma in response to anti-CD3 and IL-18, although they produced a substantial amount of IFN-gamma in response to anti-CD3 and IL-12. However, when Th1 and Th2 cells were stimulated with anti-CD3, IL-12, and IL-18, only the Th1 cells markedly augmented IFN-gamma production in response to IL-18, suggesting that IL-18 responsiveness between Th1 and Th2 cells resulted from their differential expression of IL-18R.
826 citations
TL;DR: In STAT6-deficient C57BL/6 mice treated in the same fashion, there were no eosinophilia in BAL and significantly less peribronchial inflammation than in wild- type mice, and STAT6−/− mice had much less airway reactivity than wild-type mice.
Abstract: Signal transducers and activators of transcription 6 (STAT6) is essential for interleukin 4–mediated responses, including class switching to IgE and induction of type 2 T helper cells. To investigate the role of STAT6 in allergic asthma in vivo, we developed a murine model of allergen-induced airway inflammation. Repeated exposure of actively immunized C57BL/6 mice to ovalbumin (OVA) aerosol increased the level of serum IgE, the number of eosinophils in bronchoalveolar lavage (BAL) fluid, and airway reactivity. Histological analysis revealed peribronchial inflammation with pulmonary eosinophilia in OVA-treated mice. In STAT6-deficient (STAT6−/−) C57BL/6 mice treated in the same fashion, there were no eosinophilia in BAL and significantly less peribronchial inflammation than in wild-type mice. Moreover STAT6−/− mice had much less airway reactivity than wild-type mice. These findings suggest that STAT6 plays a crucial role in the pathogenesis of allergen-induced airway inflammation.
315 citations
TL;DR: The catalytic domain of ZIP kinase is closely related to that of death-associated protein kinase (DAP kinase), which is a mediator of apoptosis induced by gamma interferon, therefore, both ZIP and DAP kinases represent a novel kinase family, which mediates apoptosis through their catalytic activities.
Abstract: We have identified a novel serine/threonine kinase, designated ZIP kinase, which mediates apoptosis. ZIP kinase contains a leucine zipper structure at its C terminus, in addition to a kinase domain at its N terminus. ZIP kinase physically binds to ATF4, a member of the activating transcription factor/cyclic AMP-responsive element-binding protein (ATF/CREB) family, through interaction between their leucine zippers. The leucine zipper domain is necessary for the homodimerization of ZIP kinase as well as for the activation of kinase. Immunostaining study showed that ZIP kinase localizes in the nuclei. Overexpression of intact ZIP kinase but not catalytically inactive kinase mutants led to the morphological changes of apoptosis in NIH 3T3 cells, suggesting that the cell death-inducing activity of ZIP kinase depends on its intrinsic kinase activity. Interestingly, the catalytic domain of ZIP kinase is closely related to that of death-associated protein kinase (DAP kinase), which is a mediator of apoptosis induced by gamma interferon. Therefore, both ZIP and DAP kinases represent a novel kinase family, which mediates apoptosis through their catalytic activities.
234 citations
TL;DR: In vitro kinase assay revealed that both DRAKs are autophosphorylated and phosphorylate myosin light chain as an exogenous substrate, although the kinase activity of D RAK2 is significantly lower than that of DRAk1.
189 citations
TL;DR: To assess the in vivo essential role of ATF4, mice lacking ATF4 are generated by gene targeting and shown to have a variety of combinatorial diversity in gene regulation.
Abstract: Background: Activating transcription factor-4 (ATF4)—also termed CREB2, C/ATF, and TAXREB67—is a basic-leucine zipper (bZip) transcription factor that belongs to the ATF/CREB family. In addition to its own family members, ATF4 can also form heterodimers with other related but distinct bZIP proteins such as the C/EBP, AP-1 and Maf families, which may give rise to a variety of combinatorial diversity in gene regulation. In order to assess the in vivo essential role of ATF4, we have generated mice lacking ATF4 by gene targeting.
Results: ATF4-deficient mice exhibited severe microphthalmia. Although ATF4-deficient eyes revealed a normal gross lens structure up to embryonic day 14.5, later on the ATF4-deficient lens, degenerated due to apoptosis without the formation of lens secondary fibre cells. Retinal development was normal in the mutant mice. The lens-specific expression of ATF4 in the mutant mice led not only to the recovery of lens secondary fibres but also to the induction of hyperplasia of these fibres.
Conclusion: These results demonstrated that ATF4 is essential for the later stages of lens fibre cell differentiation.
176 citations
TL;DR: The levels of the 90 kDa heat-shock protein (hsp90) and the activity of the hsp90beta gene promoter are increased in response to treatment by interleukin (IL)-6 and their interaction with its stress-mediated activation is discussed in terms of the multiple stimuli that may regulate the hSp90 promoter in unstressed cells.
Abstract: The levels of the 90 kDa heat-shock protein (hsp90) and the activity of the hsp90β gene promoter are increased in response to treatment by interleukin (IL)-6. The hsp90β gene promoter contains binding sites for the transcription factors nuclear factor IL-6 (NF-IL6) and signal transducer and activator of transcription 3 (STAT-3), which are activated respectively by the mitogen-activated-protein-kinase and Jak-kinase pathways following IL-6 treatment. Both these factors can activate the hsp90 promoter and have a strong synergistic effect on its activity, which appears to be critical for IL-6-mediated activation of the promoter. Interestingly, the two factors interact differently with the heat-shock factor (HSF) and a heat-shock stress. Thus STAT-3 reduces the stimulatory effect of heat shock whereas NF-IL6 enhances it. When applied together, heat shock and IL-6 produce only weak activation of the hsp90 promoter compared with either stimulus alone, indicating that the inhibitory effect of STAT-3 on HSF predominates under these conditions. In contrast, IL-1, which activates only the NF-IL6 pathway, synergizes with heat shock to produce strong activation of hsp90. These effects are discussed in terms of the multiple stimuli that may regulate the hsp90 promoter in unstressed cells and their interaction with its stress-mediated activation.
91 citations
TL;DR: It is demonstrated that Stat3 activation is required for efficient T cell proliferation by IL-2 throughIL-2Ralpha induction, which is responsible for IL-1- and IL-6-induced proliferation through distinct mechanisms.
Abstract: Stat3, a member of signal transducers and activators of transcription (STAT), is activated by a variety of cytokines. Recently, mice lacking Stat3 specifically in T cells have been generated and shown to be defective in IL-6-induced proliferation due to the impairment in IL-6-mediated prevention of apoptosis. In the present study, we show that Stat3-deficient T cells are partially defective in IL-2-induced proliferation. Stat3-deficient T cells show impaired IL-2-mediated IL-2 receptor (IL-2R) alpha chain expression. When Stat3-deficient T cells are stimulated with high-dose IL-2, these T cells express IL-2Ralpha and proliferate to similar extents as wild-type T cells. These demonstrate that Stat3 activation is required for efficient T cell proliferation by IL-2 through IL-2Ralpha induction. Taken together, these findings demonstrate that Stat3 activation in T cells is responsible for IL-2- and IL-6-induced proliferation through distinct mechanisms.
90 citations
TL;DR: Results suggest that C/EBPβ and C/ EBPδ may be involved in the transcription-dependent phase of memory formation by increasing the expression of both the DNA binding and the transcriptional activities under the direction of cAMP and/or Ca2+signaling in hippocampal neurons.
73 citations
TL;DR: Results show that L‐CCR is a novel C‐C chemokine receptor related gene induced by LPS in macrophages and may play an important role in inflammatory responses.
TL;DR: It is demonstrated that inducible expression of NF-IL6 is able to increase endogenous gene expression of macrophage inflammatory protein (MIP)-1 alpha, osteopontin and CD14 in M1 cells, and activated murine MIP-1 alpha proximal promoter luciferase construct which contains two NF- IL6 binding sites and a point mutation of either site markedly reduces theLuciferase activity.
Abstract: Nuclear factor-IL-6 (NF-IL6) belongs to the CCAAT/enhancer binding protein family of transcription factors. NF-IL6 binds to the regulatory regions of many genes induced in activated macrophages in vitro. However, which particular genes are regulated by NF-IL6 in vivo is poorly defined. In order to identify the downstream genes of NF-IL6 in a monocytic lineage, we combined an inducible expression system with subtraction cloning in a study of murine M1 monocytic leukemia cells. We demonstrated that inducible expression of NF-IL6 is able to increase endogenous gene expression of macrophage inflammatory protein (MIP)-1 alpha, osteopontin and CD14 in M1 cells. We also showed that NF-IL6 activated murine MIP-1 alpha proximal promoter luciferase construct which contains two NF-IL6 binding sites and a point mutation of either site markedly reduces the luciferase activity. These findings indicate that MIP-1 alpha is a direct target of NF-IL6.
01 Jan 1998
Patent•
25 Sep 1998
TL;DR: In this article, the authors provided a DNA coding for a serine/threonine kinase, which was shown to have an activity in SEQ ID NO: 1.
Abstract: There is provided a DNA coding for a serine/threonine kinase. Thus, the present invention provides a DNA coding for a protein (a) or (b): (a) a protein comprising the amino acid sequence as shown in SEQ ID NO: 1; (b) a protein comprising an amino acid sequence having one or several amino acids deleted, substituted or added in the amino acid sequence as shown in SEQ ID NO: 1, and exhibiting a serine/threonine kinase activity.
22 Dec 1998
DOI•
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01 Jan 1998
TL;DR: The cloning of the cDNA encoding human NF-IL6 revealed that it shows a high degree of homology with C/EBP in the carboxy-terminal basic and leucine zipper domains, responsible for DNA binding and dimerization, respectively.
Abstract: Nuclear factor for IL-6 expression (NF-IL6) was originally identified as a nuclear factor binding to a 14-bp palindromic sequence (ACATTGCACAATCT) within an interleukin (IL)-1 responsive element in the human IL-6 gene (1). The cloning of the cDNA encoding human NF-IL6 revealed that it shows a high degree of homology with C/EBP in the carboxy-terminal basic and leucine zipper domains, responsible for DNA binding and dimerization, respectively (2). NF-IL6 recognizes the same nucleotide sequences as C/EBP. Both proteins bind to a variety of the divergent nucleotide sequences with different affinity, the consensus sequence is T(T/G)NNGNNAA(T/G). The NF-IL6 gene is intronless, and produces two proteins, liver-enriched transcriptional activator protein (LAP, equivalent to NF-IL6) and liver inhibitory protein (LIP) by alternative usage of two AUG initiation codons within the same open reading frame (3). LIP contains the DNA binding and dimerization domains but is devoid of the N terminal transcriptional activation domain, and therefore behaves as an antagonist of LAP-induced transcription.