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Kimura K.,Kanazawa University | Nakamura Y.,Kanazawa University | Inaba Y.,Kanazawa University | Kido Y.,Kobe University | And 13 more authors.
Diabetes | Year: 2013

Glucose intolerance in type 2 diabetes is related to enhanced hepatic glucose production (HGP) due to the increased expression of hepatic gluconeogenic enzymes. Previously, we revealed that hepatic STAT3 decreases the expression of hepatic gluconeogenic enzymes and suppresses HGP. Here, we show that increased plasma histidine results in hepatic STAT3 activation. Intravenous and intracerebroventricular (ICV) administration of histidine-activated hepatic STAT3 reduced G6Pase protein and mRNA levels and augmented HGP suppression by insulin. This suppression of hepatic gluconeogenesis by histidine was abolished by hepatic STAT3 deficiency or hepatic Kupffer cell depletion. Inhibition of HGP by histidine was also blocked by ICV administration of a histamine H1 receptor antagonist. Therefore, histidine activates hepatic STAT3 and suppresses HGP via central histamine action. Hepatic STAT3 phosphorylation after histidine ICV administration was attenuated in histamine H1 receptor knockout (Hrh1KO) mice but not in neuron-specific insulin receptor knockout (NIRKO) mice. Conversely, hepatic STAT3 phosphorylation after insulin ICV administration was attenuated in NIRKO but not in Hrh1KO mice. These findings suggest that central histidine action is independent of central insulin action, while both have additive effects on HGP suppression. Our results indicate that central histidine/histamine-mediated suppression of HGP is a potential target for the treatment of type 2 diabetes. © 2013 by the American Diabetes Association.


Lampropoulou V.,Laboratory of Immune Regulation | Calderon-Gomez E.,Laboratory of Immune Regulation | Roch T.,Laboratory of Immune Regulation | Neves P.,Laboratory of Immune Regulation | And 5 more authors.
Immunological Reviews | Year: 2010

B lymphocytes contribute to immunity through production of antibodies, antigen presentation to T cells, and secretion of cytokines. B cells are generally considered in autoimmune diseases as drivers of pathogenesis. This view is certainly justified, given the successful utilization of the B cell-depleting reagent rituximab in patients with rheumatoid arthritis or other autoimmune pathologies. In a number of cases, however, the depletion of B cells led to an exacerbation of symptoms in patients with autoimmune disorders. In a similar manner, mice lacking B cells can develop an aggravated course of disease in several autoimmune models. These paradoxical observations are now explained by the concept that activated B cells can suppress immune responses through the production of cytokines, especially interleukin-10. Here, we review the stimulatory signals that induce interleukin-10 secretion and suppressive functions in B cells and the phenotype of the B cells with such characteristics. Finally, we formulate a model explaining how this process of immune regulation by activated B cells can confer advantageous properties to the immune system in its combat with pathogens. Altogether, this review proposes that B-cell-mediated regulation is a fundamental property of the immune system, with features of great interest for the development of new cell-based therapies for autoimmune diseases. © 2009 John Wiley & Sons A/S.


Hayasaka H.,Laboratory of Immune Regulation | Kobayashi D.,Laboratory of Immune Regulation | Yoshimura H.,Laboratory of Immune Regulation | Nakayama E.E.,Osaka University | And 3 more authors.
PLoS ONE | Year: 2015

During human immunodeficiency virus (HIV) infection, enhanced migration of infected cells to lymph nodes leads to efficient propagation of HIV-1. The selective chemokine receptors, including CXCR4 and CCR7, may play a role in this process, yet the viral factors regulating chemokine-dependent T cell migration remain relatively unclear. The functional cooperation between the CXCR4 ligand chemokine CXCL12 and the CCR7 ligand chemokines CCL19 and CCL21 enhances CCR7-dependent T cell motility in vitro as well as cell trafficking into the lymph nodes in vivo. In this study, we report that a recombinant form of a viral CXCR4 ligand, X4-tropic HIV-1 gp120, enhanced the CD4 T cell response to CCR7 ligands in a manner dependent on CXCR4 and CD4, and that this effect was recapitulated by HIV-1 virions. HIV-1 gp120 significantly enhanced CCR7-dependent CD4 T cell migration from the footpad of mice to the draining lymph nodes in in vivo transfer experiments. We also demonstrated that CXCR4 expression is required for stable CCR7 expression on the CD4 T cell surface, whereas CXCR4 signaling facilitated CCR7 ligand binding to the cell surface and increased the level of CCR7 homo- as well as CXCR4/CCR7 hetero-oligomers without affecting CCR7 expression levels. Our findings indicate that HIV-evoked CXCR4 signaling promotes CCR7-dependent CD4 T cell migration by up-regulating CCR7 function, which is likely to be induced by increased formation of CCR7 homo- and CXCR4/CCR7 hetero-oligomers on the surface of CD4 T cells. © 2015 Hayasaka et al.


PubMed | Laboratory of Immune Regulation, Osaka University and Research Institute for Microbial Diseases and
Type: Journal Article | Journal: International immunology | Year: 2016

Inappropriate activation of T helper (Th) cells, such as Th1 and Th17 cells, is implicated in the pathogenesis of chronic inflammatory disorders including ulcerative colitis (UC). CX


Hirao M.,Osaka University | Yamasaki N.,Osaka University | Oze H.,Osaka University | Ebina K.,Osaka University | And 7 more authors.
Rheumatology International | Year: 2012

Regarding the pathobiology of rheumatoid arthritis, oxidative stress induced by reactive oxygen species is an important mechanism that underlies destructive and proliferative synovitis. Abundant amounts of reactive oxygen species have been detected in the synovial fluid of inflamed rheumatoid joints. It is reported that drugs that block tumor necrosis factor-a reduce the oxidative stress marker levels in patients with rheumatoid arthritis. In this study, we measured reactive oxygen species using a free radical analytical system in patients with rheumatoid arthritis treated with disease-modifying antirheumatic drugs, tumor necrosis factor-a-blocking drugs (infliximab, etanercept), and an interleukin-6-blocking drug (tocilizumab). The serum level of oxidative stress was drastically low in patients with rheumatoid arthritis treated with tocilizumab, suggesting that interleukin-6 blocking therapy reduces not only joint damage, but also vascular degeneration in patients with rheumatoid arthritis. We believe that such a drastic effect would reduce the incidence of cardiovascular events and mortality in patients with rheumatoid arthritis. © Springer-Verlag 2011.


Caetano S.S.,Laboratory of Immune Regulation | Teixeira T.,Laboratory of Immune Regulation | Tadokoro C.E.,Laboratory of Immune Regulation
Journal of Visualized Experiments | Year: 2012

Two-photon Microscopy (TPM) provides image acquisition in deep areas inside tissues and organs. In combination with the development of new stereotactic tools and surgical procedures, TPM becomes a powerful technique to identify niches inside organs and to document cellular behaviors in live animals. While intravital imaging provides information that best resembles the real cellular behavior inside the organ, it is both more laborious and technically demanding in terms of required equipment/procedures than alternative ex vivo imaging acquisition. Thus, we describe a surgical procedure and novel stereotactic organ holder that allows us to follow the movements of Foxp3+ cells within the thymus. Foxp3 is the master regulator for the generation of regulatory T cells (Tregs). Moreover, these cells can be classified according to their origin: ie. thymus-differentiated Tregs are called naturally-occurring Tregs (nTregs), as opposed to peripherally-converted Tregs (pTregs). Although significant amount of research has been reported in the literature concerning the phenotype and physiology of these T cells, very little is known about their in vivo interactions with other cells. This deficiency may be due to the absence of techniques that would permit such observations. The protocol described in this paper provides a remedy for this situation. Our protocol consists of using nude mice that lack an endogenous thymus since they have a punctual mutation in the DNA sequence that compromises the differentiation of some epithelial cells, including thymic epithelial cells. Nude mice were gamma-irradiated and reconstituted with bone marrows (BM) from Foxp3-KI gfp/gfp mice. After BM recovery (6 weeks), each animal received embryonic thymus transplantation inside the kidney capsule. After thymus acceptance (6 weeks), the animals were anesthetized; the kidney containing the transplanted thymus was exposed, fixed in our organ holder, and kept under physiological conditions for in vivo imaging by TPM. We have been using this approach to study the influence of drugs in the generation of regulatory T cells. © 2012 Creative Commons Attribution License.


Saiga H.,Laboratory of Immune Regulation | Takeda K.,Laboratory of Immune Regulation
Kekkaku | Year: 2010

Mycobacterium tuberculosis, causing tuberculosis, is the pathogen that invades immune cells, especially macrophages, and evade from the host immune response. Recent studies have reported that M. tuberculosis also invade alveolar epithelial cells as well as alveolar macrophages. However, the role of alveolar epithelial cells in the host defense against M. tuberculosis remains unknown. In this study, we demonstrate that secretory leukocyte protease inhibitor (SLPI) and lipocalin 2 are secreted into the alveolar space by alveolar macrophages and epithelial cells during the early phase of respiratory mycobacterial infection. SLPI kills mycobacteria by enhancing the membrane permeability, and lipocalin 2 is internalized into the alveolar epithelial cells and inhibits intracellular mycobacterial growth by blocking iron uptake. Taken together, these findings highlight a pivotal role for alveolar epithelial cells during mycobacterial infection.


Hirao M.,Osaka University | Nampei A.,Osaka University | Shi K.,Osaka University | Yoshikawa H.,Osaka University | And 2 more authors.
Modern Rheumatology | Year: 2011

Two cases of subcutaneous soft tissue infection in 30 RA patients treated with tocilizumab are reported. In both patients, local redness, swelling, and heat were observed around the affected site. WBC spikes and such local findings were suggested to be clinically useful for the early detection of low-grade subcutaneous infection in RA patients whose disease is tightly controlled with tocilizumab. Of note, the C-reactive protein (CRP) level and temperature lacked clinical utility for such detection. © Japan College of Rheumatology 2011.

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