Showing papers by "Shizuo Akira published in 1996"
TL;DR: It is concluded that Stat6 plays a central role in exerting IL-4-mediated biological responses, and production of Th2 cytokines from T cells as well as IgE and IgGl responses after nematode infection were profoundly reduced.
Abstract: Interleukin-4 (IL-4) is a pleiotropic lymphokine which plays an important role in the immune system. IL-4 activates two distinct signalling pathways through tyrosine phosphorylation of Stat6, a signal transducer and activator of transcription, and of a 170K protein called 4PS. To investigate the functional role of Stat6 in IL-4 signalling, we generated mice deficient in Stat6 by gene targeting. We report here that in the mutant mice, expression of CD23 and major histocompatibility complex (MHC) class II in resting B cells was not enhanced in response to IL-4. IL-4 induced B-cell proliferation costimulated by anti-IgM antibody was abolished. The T-cell proliferative response was also notably reduced. Furthermore, production of Th2 cytokines from T cells as well as IgE and IgG1 responses after nematode infection were profoundly reduced. These findings agreed with those obtained in IL-4 deficient mice or using antibodies to IL-4 and the IL-4 receptor. We conclude that Stat6 plays a central role in exerting IL-4 mediated biological responses.
1,526 citations
TL;DR: It is demonstrated that STAT3 activation is the critical step in a cascade of events that leads to terminal differentiation of M1 cells.
Abstract: Myeloid leukemia M1 cells can be induced for growth arrest and terminal differentiation into macrophages in response to interleukin 6 (IL-6) or leukemia inhibitory factor (LIF). Recently, a large number of cytokines and growth factors have been shown to activate the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway. In the case of IL-6 and LIF, which share a signal transducing receptor gp130, STAT3 is specifically tyrosine-phosphorylated and activated by stimulation with each cytokine in various cell types. To know the role of JAK-STAT pathway in M1 differentiation, we have constructed dominant negative forms of STAT3 and established M1 cell lines that constitutively express them. These M1 cells that overexpressed dominant negative forms showed no induction of differentiation-associated markers including Fc gamma receptors, ferritin light chain, and lysozyme after treatment with IL-6. Expression of either c-myb or c-myc was not downregulated. Furthermore, IL-6- and LIF-mediated growth arrest and apoptosis were completely blocked. Thus these findings demonstrate that STAT3 activation is the critical step in a cascade of events that leads to terminal differentiation of M1 cells.
343 citations
TL;DR: The results indicate that CHOP can induce apoptosis in a p53‐independent manner and requires leucine zipper domain but neither intact basic region nor trans‐activation domain.
322 citations
Journal Article•
TL;DR: The results suggest that the macrophage functions in response to IL-13 were impaired in STAT6-deficient mice, indicating thatIL-13 and IL-4 share the signaling pathway via STAT6.
Abstract: IL-13 shares many biologic responses with IL-4. In contrast to well-characterized IL-4 signaling pathways, which utilize STAT6 and 4PS/IRS2, IL-13 signaling pathways are poorly understood. Recent studies performed with STAT6-deficient mice have demonstrated that STAT6 plays an essential role in IL-4 signaling. In this study, the functions of peritoneal macrophages of STAT6-deficient mice in response to IL-13 were analyzed. In STAT6-deficient mice, neither morphologic changes nor augmentation of MHC class II expression in response to IL-13 was observed. In addition, IL-13 did not decrease the nitric oxide production by activated macrophages. Taken together, these results suggest that the macrophage functions in response to IL-13 were impaired in STAT6-deficient mice, indicating that IL-13 and IL-4 share the signaling pathway via STAT6.
242 citations
Journal Article•
TL;DR: Differential phosphorylation and consequent differential activation of both separate and overlapping STAT proteins by IL-2, IL-12, and IFN-alpha may provide a molecular basis for the similarities and differences in the actions of these cytokines on NK cells.
Abstract: IL-2-, IL-12-, and IFN-alpha-mediated signaling pathways were analyzed in primary NK cells and in the NK3.3 cell line. Gel mobility shift and immunoprecipitation analyses revealed that in addition to activating STAT3 (signal transducer and activator of transcription-3) and STAT5, IL-2 induced tyrosine and serine phosphorylation of STAT1 alpha, which formed IFN-gamma-activated sequence-binding complexes by itself and with STAT3. Although IL-2 and IFN-alpha activated STAT1 alpha and STAT5, IL-2 predominantly activated STAT5, while IFN-alpha predominantly activated STAT1 alpha. IL-2 induced less STAT1 alpha activation and IFN-alpha induced greater STAT5 activation in NK3.3 cells compared with preactivated primary NK cells. In NK3.3 cells, IL-2 induced comparable formation of c-fos promoter sis-inducible element IFN-gamma-activated sequence-binding complexes containing STAT3 alone with complexes containing STAT3 and STAT1 alpha, while in preactivated primary NK cells, it preferentially induced complexes containing STAT3 and STAT1 alpha. Thus, signaling in NK3.3 cells is not always identical with that in primary NK cells. In contrast to IL-2 and IFN-alpha, IL-12 induced strong tyrosine phosphorylation of STAT4 and variable weak phosphorylation of STAT3. However, supershift analyses using the c-fos promoter sis-inducible element probe showed that IL-12 activated STAT4, STAT1 alpha, and STAT3, and induced complexes containing STAT4 only, STAT4 with STAT1 alpha, STAT3 with STAT1 alpha, or STAT1 alpha only in preactivated primary NK cells. STAT1 alpha activation by IL-12 correlated with increased phosphorylation of serine, but not tyrosine. Finally, IL-2 induced tyrosine phosphorylation of JAK1 and JAK3, while IL-12 induced phosphorylation of JAK2 and TYK2 in both preactivated primary NK and NK3.3 cells. Differential phosphorylation and consequent differential activation of both separate and overlapping STAT proteins by IL-2, IL-12, and IFN-alpha may provide a molecular basis for the similarities and differences in the actions of these cytokines on NK cells.
96 citations
TL;DR: The in vivo roles of interleukin‐6 and nuclear factor for interleucin-6 expression that have been revealed by gene targeting as well as recent progress in understanding the interleukain‐ 6 gene regulation and signaling pathway in macrophages are reviewed.
Abstract: Interleukin-6 is a multifunctional cytokine important for host defense. Macrophages are potent producers of interleukin-6. Conversely, interleukin-6 acts on monocytes to induce their differentiation to macrophages. This paper reviews the in vivo roles of interleukin-6 and nuclear factor for interleu
53 citations
TL;DR: The structure of the mouse STAT3 gene was almost identical to that of the human STAT2 gene, including the number and size of exons, indicating that the exon-intron organization had already been accomplished before these two genes duplicated, and then these genes evolved to respond to different ligands.
Abstract: A variety of cytoklnes Induce the tyroslne phosphorylation of signal transducers and activators of transcription (STATs). Activation of the same STAT proteins by distinct cytokines and activation of different STAT proteins by each cytokine are thought to contribute to redundancy and plelotropy of cytokine actions respectively. STAT3 is rapidly tyrosine phosphorylated in response to IL-6, ciliary neurotrophlc factor, oncostatln M, leukemia Inhibitory factor, IL-11, granulocyte colony stimulation factor and epidermal growth factor. In this report we have Isolated and characterized the mouse genomic structure of STAT3. The mouse STAT3 gene consisted of 24 exons which spanned >37 kb. The structure of the mouse STAT3 gene was almost Identical to that of the human STAT2 gene, Including the number and size of exons, indicating that the exon-intron organization had already been accomplished before these two genes duplicated, and then these genes evolved to respond to different llgands. By molecular linkage analysis with interspecific backcross mice the STAT3 gene mapped at 1.4 cM proximal to D11MH59 on mouse chromosome 11. The promoter region contained potential regulatory elements such as GATA, NF-IL-6, PEBP2, Sp-1, AP-2 binding sites, cAMP response element, CAAT box and E-box. Transient expression of constructs harboring the 5' flanking region of the STAT3 gene fused to the luciferase gene showed that a 160 bp sequence upstream of the transcription start site conferred a basal and an IL-6-induclbl e promoter activity.
31 citations
TL;DR: This paper identified alternatively spliced forms of Stat2 in human and mouse mRNAs, which contain a stop codon in SH2 domain, and therefore give rise to a short form of stat2 when the mRNA are translated.
17 citations
TL;DR: The cDNA insert of the plasmid p14-6 is found to be the 3'-untranslated region (3'-UTR) of the transcription factor for human interleukin-6, NF-IL6, which is apparently related to the reversion of the malignant cellular phenotype.
Abstract: The cDNA insert of the plasmid p14-6 is found to be the 3'-untranslated region (3'-UTR) of the transcription factor for human interleukin-6, NF-IL6. This 3'-UTR is actively transcribed in the revertant cell line RR, which contains the p14-6 plasmid integrated into its genomic DNA. Simultaneously a protein specifically bound to this 3'-UTR is expressed in significantly larger amounts. Its overexpression is apparently related to the reversion of the malignant cellular phenotype. The properties of this protein, named BNF, and possible reasons for its overexpression are discussed, and hypothesis on the mechanism of reversion of the RR cells is proposed.
10 citations
20 Jun 1996
TL;DR: In this paper, the 3'-untranslatcd region (3'-UTR) of the transcription factor for human interleukin-6, NF-IL6, was found to be the cDNA insert of the plasmid p14-6.
Abstract: The cDNA insert of the plasmid p14-6[1] is found to be the 3'-untranslatcd region (3'-UTR) of the transcription factor for human interleukin-6, NF-IL6. This 3' -DTK is actively transcribed in the revertant cell line RR, which contains the p14-6 plasmid integrated into its genomic DNA. Simultaneously a protein specifically bound to this 3'-UTR is expressed in significantly larger amounts. Its overexpression is apparently related to the reversion of the malignant cellular phenotype. The properties of this protein, named BNF, and possible reasons for its overexpression are discussed, and hypothesis on the mechanism of reversion of the RR cells is proposed.
9 citations