Cytokine Regulation of Early Lymphohematopoietic Development

Hirayama, Fumiya; Ogawa, Makio

doi:10.1002/stem.140369

Cited by 14 publications

(5 citation statements)

References 43 publications

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“…Several cytokines have been shown to promote B cell development in vitro and in vivo (25,59), but extensive studies of mice deficient in different cytokine ligands and receptors have so far failed to support an indispensable role for cytokines in B cell development. Although the production of mature B cells in the BM of IL-7 and IL-7R␣-deficient mice takes place almost exclusively during fetal and postnatal development (9,26,27,30), a stable pool of mature B cells are maintained throughout adult life in peripheral organs, sustaining normal levels of circulating Ig (9,26,27,30).…”

Section: Discussionmentioning

confidence: 99%

Complementary Signaling through flt3 and Interleukin-7 Receptor α Is Indispensable for Fetal and Adult B Cell Genesis

Sitnicka

Brakebusch

Mårtensson

et al. 2003

The Journal of Experimental Medicine

148

135

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Extensive studies of mice deficient in one or several cytokine receptors have failed to support an indispensable role of cytokines in development of multiple blood cell lineages. Whereas B1 B cells and Igs are sustained at normal levels throughout life of mice deficient in IL-7, IL-7Rα, common cytokine receptor gamma chain, or flt3 ligand (FL), we report here that adult mice double deficient in IL-7Rα and FL completely lack visible LNs, conventional IgM+ B cells, IgA+ plasma cells, and B1 cells, and consequently produce no Igs. All stages of committed B cell progenitors are undetectable in FL−/− × IL-7Rα−/− BM that also lacks expression of the B cell commitment factor Pax5 and its direct target genes. Furthermore, in contrast to IL-7Rα−/− mice, FL−/− × IL-7Rα−/− mice also lack mature B cells and detectable committed B cell progenitors during fetal development. Thus, signaling through the cytokine tyrosine kinase receptor flt3 and IL-7Rα are indispensable for fetal and adult B cell development.

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Section: Discussionmentioning

confidence: 99%

Complementary Signaling through flt3 and Interleukin-7 Receptor α Is Indispensable for Fetal and Adult B Cell Genesis

Sitnicka

Brakebusch

Mårtensson

et al. 2003

The Journal of Experimental Medicine

148

135

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“…Completely blocking IL-12 with mAbs or anti-CD40 antibodies in acute GVHD mice may have favorable results for Th1 inhibition, but at the cost of compromising immune defense and hematopoiesis soon after BMT because IL-12 plays a critical role in proliferation and differentiation of lymphohematopoietic progenitors 36 and in the activation of NK cells. 37 In fact, anti-IL-12 treatment using the anti-CD40 or anti-IL-12 antibodies did not prolong the survival of acute GVHD mice as expected.…”

Section: Discussionmentioning

confidence: 99%

Prevention of lethal acute graft-versus-host disease in mice by oral administration of T helper 1 inhibitor, TAK-603

Sakamaki

Kuroda

et al. 2001

Blood

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Acute graft-versus-host diseases (GVHD) is a major cause of morbidity and mortality in patients undergoing allogeneic bone marrow transplantation (BMT). T helper 1 (Th1)-type cytokines such as interferon-gamma or tumor necrosis factor-alpha have been implicated in the pathogenesis of acute GVHD. TAK-603 is a new quinoline derivative, which is now in clinical trials for use as a disease-modifying antirheumatic drug. In preclinical studies, it inhibited delayed-type hypersensitivity, but not Arthus-type reaction, in mice, and selectively suppressed Th1 cytokine production. Thus, the present study was designed to investigate whether the Th1 inhibitor (TAK-603) ameliorates lethal acute GVHD in a mouse model. Administration of TAK-603 into BALB/c mice given 10 Gy total body irradiation followed by transplantation of bone marrow and spleen cells from C57BL/6 mice markedly reduced the mortality in association with minimal signs of GVHD pathology in the liver, intestine, and skin. TAK-603 reduced not only the production of Th1-type cytokines, but also the proportion of Th1 cells in CD4(+) helper T cells in this GVHD mouse model. These results suggest that TAK-603 could be a potent therapeutic agent for acute lethal GVHD.

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“…In absence of GPR15, LPS-stimulated Macs expressed higher levels of Il6, Il17a, Il23, Tnfsf8, Il1b, Ifna2 and Ccnd2. These genes are involved in several cellular signalling pathways including IL-17 differentiation (33), haematopoiesis (37), cytokine interaction network (34), chemokine-chemokine receptor interaction and Jak-STAT signalling pathways (38)(39). On the contrary, GPR15 KO Macs failed to down-regulate expression of Ccl17, Itgax, Nrp1 and Rasgrf2, which are involved in activation, migration and proliferation of immune cells (40)(41)(42)(43).…”

Section: What Does This Paper Add?mentioning

confidence: 99%

The fifth epidermal growth factor like region of thrombomodulin alleviates LPS-induced sepsis through interacting with GPR15

Pan¹,

Wang²,

Kojima³

et al. 2017

Thromb Haemost

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Thrombomodulin (TM) exerts cytoprotection via the fifth region of epidermal growth factor (EGF)-like domain of TM (TME5) by interacting with G-protein coupled receptor 15 (GPR15) expressed on cell surface of vascular endothelial cells. TM is also implied to mediate anti-inflammatory functions by unknown mechanism. By applying a lipopolysaccharide (LPS)-induced murine sepsis model, we assessed the role of TME5 in septic inflammation and coagulation. We found that TME5 treatment protected mice in association with ameliorating inflammation and coagulopathy in LPS-induced sepsis. Further study confirmed that TME5 bound GPR15 in vitro. Knock out of GPR15 abolished protective role of TME5 in sepsis model. GPR15 mediated anti-inflammatory function of TME5 through suppression of phosphorylation of IκBα, nuclear translocation of NF-κB and release of pro-inflammatory cytokines in macrophages (Macs). Knock out of GPR15 resulted in dysregulated immune response of Macs, characterised by excessive expression of pro-inflammatory genes and failing to limit immune response. This study indicates that TME5 exerts anti-inflammatory function through inhibition of NF-κB in a GPR15-dependent manner. The use of TME5 may be a potential therapeutic option for treatment of sepsis.

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Cytokine Regulation of Early Lymphohematopoietic Development

Cited by 14 publications

References 43 publications

Complementary Signaling through flt3 and Interleukin-7 Receptor α Is Indispensable for Fetal and Adult B Cell Genesis

Complementary Signaling through flt3 and Interleukin-7 Receptor α Is Indispensable for Fetal and Adult B Cell Genesis

Prevention of lethal acute graft-versus-host disease in mice by oral administration of T helper 1 inhibitor, TAK-603

The fifth epidermal growth factor like region of thrombomodulin alleviates LPS-induced sepsis through interacting with GPR15

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