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1-6 of 6
Shin-Ichi Nishikawa
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Journal Articles
Kenya Honda, Hiroyasu Nakano, Hisahiro Yoshida, Satomi Nishikawa, Paul Rennert, Koichi Ikuta, Masakatsu Tamechika, Kazuhito Yamaguchi, Tetsuo Fukumoto, Tsutomu Chiba, Shin-Ichi Nishikawa
Journal:
Journal of Experimental Medicine
Journal of Experimental Medicine (2001) 193 (5): 621–630.
Published: 05 March 2001
Abstract
Mice deficient in lymphotoxin β receptor (LTβR) or interleukin 7 receptor α (IL-7Rα) lack Peyer's patches (PPs). Deficiency in CXC chemokine receptor 5 (CXCR5) also severely affects the development of PPs. A molecular network involving these three signaling pathways has been implicated in PP organogenesis, but it remains unclear how they are connected during this process. We have shown that PP organogenesis is initiated at sites containing IL-7Rα + lymphoid cells and vascular cell adhesion molecule (VCAM)-1/intercellular adhesion molecule (ICAM)-1 expressing nonlymphoid elements. Here we characterize these lymphoid and nonlymphoid components in terms of chemokine signals. The lymphoid population expresses CXCR5 and has a strong chemotactic response to B lymphocyte chemoattractant (BLC). Importantly, chemokines produced by VCAM-1 + ICAM-1 + nonlymphoid cells mediate the recruitment of lymphoid cells. Furthermore, we show that these VCAM-1 + ICAM-1 + cells are mesenchymal cells that are activated by lymphoid cells through the LTβR to express adhesion molecules and chemokines. Thus, promotion of PP development relies on mutual interaction between mesenchymal and lymphoid cells.
Journal Articles
Hitoshi Nagaoka, Yoshimasa Takahashi, Reiko Hayashi, Tohru Nakamura, Kumiko Ishii, Junichiro Matsuda, Atsuo Ogura, Yumiko Shirakata, Hajime Karasuyama, Tetsuo Sudo, Shin-Ichi Nishikawa, Takeshi Tsubata, Tsuguo Mizuochi, Toshihiko Asano, Hitoshi Sakano, Toshitada Takemori
Journal:
Journal of Experimental Medicine
Journal of Experimental Medicine (2000) 192 (2): 171–182.
Published: 10 July 2000
Abstract
Ras is essential for the transition from early B cell precursors to the pro-B stage, and is considered to be involved in the signal cascade mediated by pre-B cell antigen receptors. To examine the role of p21 ras in the late stage of B cell differentiation, we established transgenic mice (TG) expressing a dominant-inhibitory mutant of Ha-ras (Asn-17 Ha-ras ) in B lineage cells at high levels after the early B cell precursor stage. Expression of p21 Asn-17 Ha-ras was associated with a prominent reduction in the number of late pre-B cells, but had little effect on proliferation of early pre-B cells. Inhibition of p21 ras activity markedly reduced the life span of pre-B cells, due, at least in part, to downregulation of the expression of an antiapoptotic protein, Bcl-xL. Thus, the apparent role for p21 ras activity in pre-B cell survival may explain the decreased numbers of late pre-B cells in Asn-17 Ha-ras TG. Consistent with this possibility, overexpression of Bcl-2 in Asn-17 Ha-ras TG reversed the reduction in the number of late pre-B cells undergoing immunoglobulin light chain gene ( IgL ) rearrangement and progressing to immature B cells. These results suggest that p21 ras mediates effector pathways responsible for pre-B cell survival, which is essential for progression to the late pre-B and immature B stages.
Journal Articles
Shumpei Niida, Masato Kaku, Hitoshi Amano, Hisahiro Yoshida, Hiroshi Kataoka, Satomi Nishikawa, Kazuo Tanne, Norihiko Maeda, Shin-Ichi Nishikawa, Hiroaki Kodama
Journal:
Journal of Experimental Medicine
Journal of Experimental Medicine (1999) 190 (2): 293–298.
Published: 19 July 1999
Abstract
We demonstrated previously that a single injection of recombinant human macrophage colony-stimulating factor (rhM-CSF) is sufficient for osteoclast recruitment and survival in osteopetrotic ( op/op ) mice with a deficiency in osteoclasts resulting from a mutation in M-CSF gene. In this study, we show that a single injection of recombinant human vascular endothelial growth factor (rhVEGF) can similarly induce osteoclast recruitment in op/op mice. Osteoclasts predominantly expressed VEGF receptor 1 (VEGFR-1), and activity of recombinant human placenta growth factor 1 on osteoclast recruitment was comparable to that of rhVEGF, showing that the VEGF signal is mediated through VEGFR-1. The rhM-CSF–induced osteoclasts died after injections of VEGFR-1/Fc chimeric protein, and its effect was abrogated by concomitant injections of rhM-CSF. Osteoclasts supported by rhM-CSF or endogenous VEGF showed no significant difference in the bone-resorbing activity. op/op mice undergo an age-related resolution of osteopetrosis accompanied by an increase in osteoclast number. Most of the osteoclasts disappeared after injections of anti-VEGF antibody, demonstrating that endogenously produced VEGF is responsible for the appearance of osteoclasts in the mutant mice. In addition, rhVEGF replaced rhM-CSF in the support of in vitro osteoclast differentiation. These results demonstrate that M-CSF and VEGF have overlapping functions in the support of osteoclastic bone resorption.
Journal Articles
Masaki Hikida, Yasunori Nakayama, Yumi Yamashita, Yoshio Kumazawa, Shin-Ichi Nishikawa, Hitoshi Ohmori
Journal:
Journal of Experimental Medicine
Journal of Experimental Medicine (1998) 188 (2): 365–372.
Published: 20 July 1998
Abstract
Mouse germinal center (GC) B cells have been shown to undergo secondary V(D)J (V, variable; D, diversity; J, joining) recombination (receptor editing) mediated by the reexpressed products of recombination activating gene ( RAG ) -1 and RAG-2 . We show here that interleukin (IL)-7 as well as IL-4 was effective in inducing functional RAG products in mouse IgD + B cells activated via CD40 in vitro. Blocking of the IL-7 receptor (IL-7R) by injecting an anti– IL-7R monoclonal antibody resulted in a marked suppression of the reexpression of RAG-2 and subsequent V(D)J recombination in the draining lymph node of immunized mice, whereas RAG-2 expression was not impaired in immunized IL-4–deficient mice. Further, these peripheral B cells activated in vitro or in vivo were found to express IL-7R. These findings indicate a novel role for IL-7 and IL-7R in inducing receptor editing in GC B cells.
Journal Articles
Takahiro Kunisada, Shu-Zhuang Lu, Hisahiro Yoshida, Satomi Nishikawa, Shin-ichi Nishikawa, Masako Mizoguchi, Shin-ichi Hayashi, Lynda Tyrrell, David A. Williams, Xiaomei Wang, B. Jack Longley
Journal:
Journal of Experimental Medicine
Journal of Experimental Medicine (1998) 187 (10): 1565–1573.
Published: 18 May 1998
Abstract
The growth and differentiation of mast cells and melanocytes require stem cell factor (SCF), the ligand for the kit receptor tyrosine kinase. SCF may exist as a membrane-bound or soluble molecule. Abnormalities of the SCF-kit signaling pathway, with increased local concentrations of soluble SCF, have been implicated in the pathogenesis of the human disease cutaneous mastocytosis, but have not yet been shown to play a causal role. To investigate both the potential of SCF to cause mastocytosis and its role in epidermal melanocyte homeostasis, we targeted the expression of SCF to epidermal keratinocytes in mice with two different transgenes controlled by the human keratin 14 promoter. The transgenes contained cDNAs that either produced SCF, which can exist in both membrane-bound and soluble forms, or SCF, which remains essentially membrane bound. Murine epidermal keratinocyte expression of membrane-bound/ soluble SCF reproduced the phenotype of human cutaneous mastocytosis, with dermal mast cell infiltrates and epidermal hyperpigmentation, and caused the maintenance of a population of melanocytes in the interadnexal epidermis, an area where melanocytes and melanin are found in human skin but where they are not typically found in murine skin. Expression of membrane-bound SCF alone resulted in epidermal melanocytosis and melanin production, but did not by itself cause mastocytosis. We conclude, first, that a phenotype matching that of human mastocytosis can be produced in mice by keratinocyte overproduction of soluble SCF, suggesting a potential cause of this disease. Second, we conclude that keratinocyte expression of membrane-bound SCF results in the postnatal maintenance of epidermal melanocytes in mice. Since the resulting animals have skin that more closely approximates human skin than do normal mice, their study may be more relevant to human melanocyte biology than the study of skin of normal mice.
Journal Articles
Journal:
Journal of Experimental Medicine
Journal of Experimental Medicine (1996) 184 (6): 2301–2310.
Published: 01 December 1996
Abstract
The establishment of culture conditions that selectively support hematopoietic stem cells is an important goal of hematology. In this study, we investigated the possibility of using for this purpose a defined medium, mSFO2, which was developed for stromal cell–dependent bone marrow cultures. We found that a combination of epidermal growth factor (EGF), the OP9 stromal cell line, which lacks macrophage colony-stimulating factor, recombinant stem cell factor, and the chemically defined medium mSFO2 provides a microenvironment where c-Kit + Thy-1 +/lo Mac-1 +/lo B220 − TER119 − commonβ + IL-2R γ + gp130 + cells are selectively propagated from normal, unfractionated bone marrow cells. This cell population produced an in vitro colony at a very high efficiency (50%), whereas it has only limited proliferative ability in the irradiated recipient. Thus, the cells selected in this culture condition might represent colony-forming units in culture (CFU-c) with short-term reconstituting ability. Transferring this cell population into medium containing differentiation signals resulted in the rapid production of mature myelomonocytic and B cell lineages in vitro and in vivo. The fact that a similar culture condition was created by erb-B2–transduced OP9 in the absence of EGF indicated that EGF exerts its effect by acting on OP9 rather than directly on CFU-c. These results suggested that the balance between self-renewal and differentiation of CFU-c can be regulated by extracellular signals.