REVIEW

Role of Notch signaling in regulating innate immunity and inflammation in health and disease

  • Yingli Shang 1 ,
  • Sinead Smith 2 ,
  • Xiaoyu Hu , 1
Expand
  • 1. School of Medicine and Institute for Immunology, Tsinghua University, Beijing 100084, China
  • 2. Department of Clinical Medicine, Trinity College Dublin, Dublin 2, Ireland

Received date: 01 Jan 2016

Accepted date: 26 Jan 2016

Published date: 13 Apr 2016

Copyright

2014 This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

The Notch signaling pathway is conserved from Drosophila to mammals and is critically involved in developmental processes. In the immune system, it has been established that Notch signaling regulates multiple steps of T and B cell development in both central and peripheral lymphoid organs. Relative to the well documented role of Notch signaling in lymphocyte development, less is known about its role in regulating myeloid lineage development and function, especially in the context of acute and chronic inflammation. In this review article, we will describe the evidence accumulated during the recent years to support a key regulatory role of the Notch pathway in innate immune and inflammatory responses and discuss the potential implications of such regulation for pathogenesis and therapy of inflammatory disorders.

Cite this article

Yingli Shang , Sinead Smith , Xiaoyu Hu . Role of Notch signaling in regulating innate immunity and inflammation in health and disease[J]. Protein & Cell, 2016 , 07(03) : 159 -174 . DOI: 10. 1007/s13238-016-0250-0

1
Aguilera C, Hoya-Arias R, Haegeman G, Espinosa L, Bigas A (2004) Recruitment ofIkappaBalphato thehes1promoterisassociatedwith transcriptional repression. Proc Natl Acad SciUSA 101:16537–16542

2
Amsen D, Blander JM, Lee GR, Tanigaki K, Honjo T (2004) Instruction of distinct CD4 T helper cell fates by different notch ligands on antigen-presenting cells. Cell 117:515–526

DOI

3
Amsen D, Antov A, Jankovic D, Sher A, Radtke F(2007) Direct regulation of Gata3 expression determines theT helper differentiation potential of Notch. Immunity 27:89–99

DOI

4
Ando K, Kanazawa S, Tetsuka T, Ohta S, Jiang X (2003) Induction of Notch signaling by tumor necrosis factor in rheumatoid synovial fibroblasts. Oncogene 22:7796–7803

DOI

5
Aoyama T, Takeshita K, Kikuchi R, Yamamoto K, Cheng XW (2009) gamma-Secretase inhibitor reduces diet-induced atherosclerosis in apolipoprotein E-deficient mice. Biochem Biophys Res Commun 383:216–221

DOI

6
Bai S, Kopan R, Zou W, Hilton MJ, Ong CT (2008) NOTCH1 regulates osteoclastogenesis directly in osteoclastprecursors and indirectly via osteoblast lineage cells. JBiol Chem 283:6509–6518

DOI

7
Bansal K, Narayana Y, Patil SA, Balaji KN (2009) M. bovis BCG induced expression of COX-2 involves nitric oxide-dependent and-independent signalingpathways. JLeukoc Biol 85:804–816

DOI

8
Bigas A, Martin DI, Milner LA (1998) Notch1 and Notch2 inhibit myeloid differentiation in response to different cytokines. Mol Cell Biol 18:2324–2333

DOI

9
Bigas A, Robert-Moreno A, Espinosa L(2010) The Notch pathwayin the developing hematopoietic system. IntJDev Biol 54:1175–1188

10
Blanpain C, Lowry WE, Pasolli HA, Fuchs E(2006) Canonical notch signaling functions as a commitment switch in the epidermal lineage. Genes Dev 20:3022–3035

DOI

11
Borggrefe T, Oswald F (2009) The Notch signaling pathway: transcriptional regulation at Notch target genes. Cell Mol Life Sci 66:1631–1646

DOI

12
Bozkulak EC, Weinmaster G (2009) Selective use of ADAM10 and ADAM17 in activation ofNotch1 signaling. Mol Cell Biol 29:5679–5695

DOI

13
Carlesso N, Aster JC, Sklar J, Scadden DT (1999) Notch1-induced delay of human hematopoietic progenitor cell differentiation is associated with altered cell cycle kinetics. Blood 93:838–848

14
Caton ML, Smith-Raska MR, Reizis B(2007) Notch-RBP-J signaling controls the homeostasis of CD8-dendritic cells in the spleen. J Exp Med 204:1653–1664

DOI

15
Cheng P, Gabrilovich D(2008) Notch signaling in differentiation and function of dendritic cells. Immunol Res 41:1–14

DOI

16
Cheng P, Zlobin A, Volgina V, Gottipati S, Osborne B (2001) Notch-1 regulates NF-kappaB activity in hemopoietic progenitor cells. J Immunol 167:4458–4467

DOI

17
Cheng P, Nefedova Y, Miele L, Osborne BA, Gabrilovich D (2003) Notch signalingis necessary but not sufficient for differentiation of dendritic cells. Blood 102:3980–3988

DOI

18
Cheng P, Nefedova Y, Corzo CA, Gabrilovich DI (2007) Regulation of dendritic-cell differentiation by bone marrow stroma via different Notch ligands. Blood 109:507–515

DOI

19
Dees C, Zerr P, Tomcik M, Beyer C, Horn A(2011) Inhibitionof Notch signaling prevents experimental fibrosis and induces regression of established fibrosis. Arthritis Rheum 63:1396–1404

DOI

20
Demehri S, Liu Z, Lee J, Lin MH, Crosby SD (2008) Notch-deficient skin induces a lethal systemic B-lymphoproliferative disorder by secreting TSLP, a sentinel for epidermal integrity. PLoS Biol 6:e123

21
Dontje W, Schotte R, Cupedo T, Nagasawa M, Scheeren F (2006) Delta-like1-induced Notch1 signalingregulates the human plasmacytoid dendritic cell versusT-cell lineage decision through control of GATA-3 and Spi-B. Blood 107:2446–2452

DOI

22
Dumortier A, Durham AD, Di Piazza M, Vauclair S, Koch U (2010) Atopic dermatitis-like disease and associated lethal myeloproliferative disorder arise from loss of Notch signaling in the murine skin. PLoS One 5:e9258

23
Eagar TN, Tang Q, Wolfe M, He Y, Pear WS(2004)Notch1signaling regulatesperipheralTcell activation. Immunity 20:407–415

24
Engin F, Yao Z, Yang T, Zhou G, Bertin T(2008) Dimorphic effects of Notch signaling in bone homeostasis. Nat Med 14:299–305

DOI

25
Espinosa L, Cathelin S, D’Altri T, Trimarchi T, Statnikov A(2010) The Notch/Hes1 pathway sustains NF-kappaBactivation through CYLD repression inTcell leukemia. Cancer Cell 18:268–281

DOI

26
Fang TC, Yashiro-Ohtani Y, Del Bianco C, Knoblock DM, Blacklow SC (2007) Notch directly regulates Gata3 expression during T helper2 cell differentiation. Immunity 27:100–110

DOI

27
Feng F, Wang YC, Hu XB, Liu XW, Ji G (2010)The transcription factor RBP-J-mediated signalingis essential for dendritic cells to evoke efficient anti-tumor immune responsesin mice. Mol Cancer 9:90

DOI

28
Ferrero I, Held W, Wilson A, Tacchini-Cottier F, Radtke F(2002) Mouse CD11c(+) B220(+) Gr1(+) plasmacytoid dendritic cells develop independently of the T-cell lineage. Blood 100:2852–2857

DOI

29
Foldi J, Chung AY, Xu H, Zhu J, Outtz HH (2010) Autoamplification of Notch signaling in macrophages by TLR-induced and RBP-J-dependent induction of Jagged1. J Immunol 185:5023–5031

DOI

30
Franklin RA, Liao W, Sarkar A, Kim MV, Bivona MR(2014)The cellular and molecular origin of tumor-associated macrophages. Science 344:921–925

DOI

31
Fukushima H, Nakao A, Okamoto F, Shin M, Kajiya H (2008) The association of Notch2 and NF-kappaB accelerates RANKL-induced osteoclastogenesis. Mol Cell Biol 28:6402–6412

DOI

32
Fung E, Tang SM, Canner JP, Morishige K, Arboleda-Velasquez JF (2007) Delta-like4induces notch signaling in macrophages: implications for inflammation. Circulation 115:2948–2956

DOI

33
Gibb DR, El Shikh M, Kang DJ, Rowe WJ, El Sayed R (2010) ADAM10 is essential for Notch2-dependent marginal zoneBcell development and CD23 cleavage in vivo. J Exp Med 207:623–635

DOI

34
Goh F, Irvine KM, Lovelace E, Donnelly S, Jones MK (2009) Selective induction of the Notch ligand Jagged-1 in macrophages by soluble egg antigen from Schistosoma mansoni involves ERK signalling. Immunology 127:326–337

DOI

35
Hamidi H, Gustafason D, Pellegrini M, Gasson J(2011) Identification of novel targets of CSL-dependent Notch signaling in hematopoiesis. PLoS One 6:e20022

36
Han W, Ye Q, Moore MA (2000)Asoluble formof human Delta-like-1 inhibits differentiation of hematopoietic progenitor cells. Blood 95:1616–1625

37
Hass MR, Sato C, Kopan R, Zhao G (2009) Presenilin: RIP and beyond. Semin Cell Dev Biol 20:201–210

DOI

38
Hilton MJ, Tu X, Wu X, Bai S, Zhao H (2008) Notch signaling maintains bone marrow mesenchymal progenitors by suppressing osteoblast differentiation. Nat Med 14:306–314

DOI

39
Hoffman C, Park SH, Daley E, Emson C, Louten J (2011) Interleukin-19: a constituent of the regulome that controls antigen presenting cells in the lungs and airway responses to microbial products. PLoS One 6:e27629

40
Hoyne GF, Le Roux I, Corsin-Jimenez M, Tan K, Dunne J (2000) Serrate1-induced notch signalling regulates the decision between immunity and tolerance made by peripheral CD4(+) T cells. Int Immunol 12:177–185

DOI

41
Hu X, Ivashkiv LB (2009) Cross-regulation of signaling pathways by interferon-gamma: implications for immune responses and autoimmune diseases. Immunity 31:539–550

DOI

42
Hu X, Chung AY, Wu I, Foldi J, Chen J (2008) Integrated regulationofToll-like receptor responsesbyNotch and interferon-gamma pathways. Immunity 29:691–703

DOI

43
Ishii H, Nakazawa M, Yoshino S, Nakamura H, Nishioka K (2001) Expression of notch homologues in the synovium of rheumatoid arthritis and osteoarthritis patients. Rheumatol Int 21:10–14

DOI

44
Iso T, Kedes L, Hamamori Y (2003) HES and HERP families: multiple effectors of the Notch signaling pathway. J Cell Physiol 194:237–255

DOI

45
Ito T, Schaller M, Hogaboam CM, Standiford TJ, Sandor M (2009) TLR9 regulates the mycobacteria-elicited pulmonary granulomatous immune response in mice through DC-derived Notch ligand delta-like 4. J Clin Invest 119:33–46

46
Ito T, Allen RM, Carson WFT, Schaller M, Cavassani KA(2011) The critical roleof Notch ligand Delta-like1in the pathogenesisof influenzaA virus (H1N1) infection. PLoS Pathog 7:e1002341

47
Izon DJ, Aster JC, He Y, Weng A, Karnell FG (2002) Deltex1 redirects lymphoid progenitors to the B cell lineage by antagonizing Notch1. Immunity 16:231–243

DOI

48
Jaiswal MK, Agrawal V, Pamarthy S, Katara GK, Kulshrestha A (2015) Notch Signaling in Inflammation-Induced Preterm Labor. Sci Rep 5:15221

DOI

49
Jiao Z, Wang W, Guo M, Zhang T, Chen L (2010) Expression analysis of Notch-related molecules in peripheral bloodT helper cells of patients with rheumatoid arthritis. Scand J Rheumatol 39:26–32

DOI

50
Kapoor N, Narayana Y, Patil SA, Balaji KN (2010) Nitric oxide is involved in Mycobacterium bovis Bacillus calmette-guerin-activated Jagged1 and Notch1 signaling. JImmunol 184:3117–3126

DOI

51
Klinakis A, Lobry C, Abdel-Wahab O, Oh P, Haeno H(2011)A novel tumour-suppressor function for the Notch pathway in myeloid leukaemia. Nature 473:230–233

DOI

52
Kopan R, Ilagan MX (2009) The canonical Notch signalingpathway: unfolding the activation mechanism. Cell 137:216–233

DOI

53
Kumano K, Chiba S, Shimizu K, Yamagata T, Hosoya N(2001) Notch1 inhibits differentiation of hematopoietic cells by sustaining GATA-2 expression. Blood 98:3283–3289

DOI

54
Lam LT, Ronchini C, Norton J, Capobianco AJ, Bresnick EH (2000) Suppression of erythroid but not megakaryocytic differentiation of human K562 erythroleukemic cells by notch-1. J Biol Chem 275:19676–19684

DOI

55
Lewis KL, Caton ML, Bogunovic M, Greter M, Grajkowska LT (2011) Notch2 receptor signaling controls functional differentiation of dendritic cells in the spleen and intestine. Immunity 35:780–791

DOI

56
Li S, Miller CH, Giannopoulou E, Hu X, Ivashkiv LB (2014) RBPJ imposes a requirement for ITAM-mediated costimulation of osteoclastogenesis. J Clin Invest 124:5057–5073

DOI

57
Maekawa Y, Tsukumo S, Chiba S, Hirai H, Hayashi Y (2003) Delta1-Notch3 interactions bias the functional differentiation of activated CD4+Tcells. Immunity 19:549–559

DOI

58
Maillard I, Fang T, Pear WS (2005) Regulation of lymphoid development, differentiation, and functionby the Notch pathway. Annu Rev Immunol 23:945–974

DOI

59
Maniati E, Bossard M, Cook N, Candido JB, Emami-Shahri N (2011) Crosstalk between the canonical NF-kappaB and Notch signaling pathways inhibits Ppargamma expression and promotes pancreatic cancer progression in mice. J Clin Invest 121:4685–4699

DOI

60
Martinez Arias A, Zecchini V, Brennan K (2002) CSL-independent Notch signalling: a checkpoint in cell fate decisions during development? Curr Opin Genet Dev 12:524–533

61
Milner LA, Bigas A, Kopan R, Brashem-Stein C, Bernstein ID (1996) Inhibition of granulocytic differentiation by mNotch1. Proc Natl Acad Sci USA 93:13014–13019

DOI

62
Mizutani K, Matsubayashi T, Iwase S, Doi TS, Kasai K (2000) Murine Delta homologue, mDelta1, expressed on feeder cells controls cellular differentiation. Cell Struct Funct 25:21–31

DOI

63
Monsalve E, Perez MA, Rubio A, Ruiz-Hidalgo MJ, Baladron V (2006) Notch-1 up-regulation and signaling following macrophage activation modulates gene expression patterns known to affect antigen-presenting capacity and cytotoxic activity. J Immunol 176:5362–5373

DOI

64
Monsalve E, Ruiz-Garcia A, Baladron V, Ruiz-Hidalgo MJ, Sanchez-Solana B (2009) Notch1 upregulates LPS-induced macrophage activation by increasing NF-kappaB activity. Eur J Immunol 39:2556–2570

DOI

65
Murea M, Park JK, Sharma S, Kato H, Gruenwald A (2010) Expression of Notch pathway proteins correlates with albuminuria, glomerulosclerosis, and renal function. Kidney Int 78:514–522

DOI

66
Murthy A, Shao YW, Narala SR, Molyneux SD, Zuniga-Pflucker JC (2012) Notch Activation by the Metalloproteinase ADAM17 Regulates Myeloproliferation and Atopic Barrier Immunity by Suppressing Epithelial Cytokine Synthesis. Immunity 36:105–119

DOI

67
Nakazawa M, Ishii H, Aono H, Takai M, Honda T (2001a) Role of Notch-1 intracellular domain in activation of rheumatoid synoviocytes. Arthritis Rheum 44:1545–1554

68
Nakazawa M, Ishii H, Nakamura H, Yoshino SI, Fukamizu A (2001b) NFkappaB2 (p52) promoter activation via Notch signaling pathway in rheumatoid synoviocytes. Int J Mol Med 7:31–35

69
Narayana Y, Balaji KN (2008) NOTCH1 up-regulation and signaling involved in Mycobacterium bovis BCG-induced SOCS3 expression in macrophages. J Biol Chem 283:12501–12511

DOI

70
Ohishi K, Varnum-Finney B, Serda RE, Anasetti C, Bernstein ID (2001) The Notch ligand, Delta-1, inhibits the differentiation of monocytes into macrophages but permits their differentiation into dendritic cells. Blood 98:1402–1407

DOI

71
Olivier A, Lauret E, Gonin P, Galy A(2006) The Notch ligand delta-1 is a hematopoietic development cofactor for plasmacytoid dendritic cells. Blood 107:2694–2701

DOI

72
Ong CT, Sedy JR, Murphy KM, Kopan R(2008)Notchand presenilin regulate cellular expansion and cytokine secretion but cannot instruct Th1/Th2 fate acquisition. PLoS One 3:e2823

73
Osborne BA, Minter LM (2007) Notch signalling during peripheral T-cell activation and differentiation. Nat Rev Immunol 7:64–75

DOI

74
Osipo C, Golde TE, Osborne BA, Miele LA (2008) Off the beaten pathway: the complex cross talk between Notch and NF-kappaB. Lab Invest 88:11–17

DOI

75
Ostroukhova M, Qi Z, Oriss TB, Dixon-McCarthy B, Ray P (2006)Treg-mediated immunosuppression involves activation of the Notch-HES1 axis by membrane-bound TGF-beta. J Clin Invest1 16:996–1004

DOI

76
Ottaviani S, Tahiri K, Frazier A, Hassaine ZN, Dumontier MF (2010) Hes1, a new target for interleukin 1beta in chondrocytes. Ann Rheum Dis 69:1488–1494

DOI

77
Outtz HH, Wu JK, Wang X, Kitajewski J (2010) Notch1 deficiency results in decreased inflammation during wound healing and regulates vascular endothelial growth factor receptor-1 and inflammatory cytokine expression in macrophages. J Immunol 185:4363–4373

DOI

78
Palaga T, Buranaruk C, Rengpipat S, Fauq AH, Golde TE (2008) Notch signaling is activated by TLR stimulation and regulates macrophage functions. EurJ Immunol 38:174–183

DOI

79
Palomero T, Lim WK, Odom DT, Sulis ML, Real PJ (2006) NOTCH1 directly regulates c-MYC and activates a feed-forwardloop transcriptional network promoting leukemic cell growth. Proc Natl Acad Sci USA 103:18261–18266

DOI

80
Park JS, Kim SH, Kim K, Jin CH, Choi KY (2015) Inhibition of notch signalling ameliorates experimental inflammatory arthritis. Ann Rheum Dis 74:267–274

DOI

81
Radtke F, Wilson A, Stark G, Bauer M, van Meerwijk J (1999) Deficient T cell fate specification in mice with an induced inactivation of Notch1. Immunity 10:547–558

DOI

82
Radtke F, Ferrero I, Wilson A, Lees R, Aguet M (2000) Notch1 deficiency dissociates the intrathymic development of dendritic cells andTcells. J Exp Med 191:1085–1094

DOI

83
Radtke F, Fasnacht N, Macdonald HR (2010) Notch signalingin the immune system. Immunity 32:14–27

DOI

84
Rangarajan A, Talora C, Okuyama R, Nicolas M, Mammucari C (2001) Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation. EMBO J 20:3427– 3436

DOI

85
Sathe P, Wu L (2011) The network of cytokines, receptors and transcription factors governing the development of dendritic cell subsets. Protein Cell 2:620–630

DOI

86
Schaller MA, Neupane R, Rudd BD, Kunkel SL, Kallal LE (2007) Notch ligand Delta-like4 regulates disease pathogenesis during respiratory viral infections by modulating Th2 cytokines. J Exp Med 204:2925–2934

DOI

87
Schroeder T, Just U (2000) Notch signalling via RBP-J promotes myeloid differentiation. EMBOJ 19:2558–2568

DOI

88
Sekine C, Moriyama Y, Koyanagi A, Koyama N, Ogata H(2009) Differential regulation ofsplenic CD8-dendritic cells and marginal zoneB cellsby Notch ligands. Int Immunol 21:295–301

DOI

89
Sekine C, Koyanagi A, Koyama N, Hozumi K, Chiba S (2012) Differential regulation of osteoclastogenesis by Notch2/Delta-like 1 and Notch1/Jagged1 axes. Arthritis Res Ther 14:R45

90
Shackel NA, McGuinness PH, Abbott CA, Gorrell MD, McCaughan GW (2001) Identification of novel molecules and pathogenic pathways in primary biliary cirrhosis: cDNA array analysis of intrahepatic differential gene expression. Gut 49:565–576

DOI

91
Skokos D, Nussenzweig MC (2007) CD8-DCs induce IL-12independent Th1 differentiation through Delta4Notch-like ligand in response to bacterial LPS. J Exp Med 204:1525–1531

DOI

92
Stahl EA, Raychaudhuri S, Remmers EF, Xie G, Eyre S(2010) Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat Genet 42:508–514

DOI

93
Swarnkar G, Karuppaiah K, Mbalaviele G, Chen TH, Abu-Amer Y (2015) Osteopetrosis in TAK1-deficient mice owing to defective NF-kappaB and NOTCH signaling. Proc Natl Acad Sci USA 112:154–159

DOI

94
Tanigaki K, Honjo T (2007) Regulation of lymphocyte development by Notch signaling. Nat Immunol 8:451–456

DOI

95
Tan-Pertel HT, Walker L, Browning D, Miyamoto A, Weinmaster G (2000) Notch signaling enhances survival and alters differentiation of 32D myeloblasts. J Immunol 165:4428–4436

DOI

96
Tsao PN, Wei SC, Huang MT, Lee MC, Chou HC (2011) Lipopolysaccharide-induced Notch signaling activation through JNK-dependent pathway regulates inflammatory response. J Biomed Sci 18:56

DOI

97
Varnum-Finney B, Purton LE, Yu M, Brashem-Stein C, Flowers D (1998) The Notch ligand, Jagged-1, influences the development of primitive hematopoietic precursor cells. Blood 91:4084–4091

98
Varnum-Finney B, Brashem-Stein C, Bernstein ID (2003) Combined effects of Notch signaling and cytokines induce a multiple log increase in precursors with lymphoid and myeloid reconstituting ability. Blood 101:1784–1789

DOI

99
Wang YC, Hu XB, He F, Feng F, Wang L (2009) Lipopolysaccharide-induced maturation of bone marrow-derived dendritic cells is regulated by notch signaling through the up-regulation of CXCR4. J Biol Chem 284:15993–16003

DOI

100
Wang YC, He F, Feng F, Liu XW, Dong GY (2010) Notch signaling determines the M1 versus M2 polarization of macrophages in antitumor immune responses. Cancer Res 70:4840–4849

DOI

101
Wang H, Zou J, Zhao B, Johannsen E, Ashworth T (2011) Genome-wide analysis reveals conserved and divergent features of Notch1/RBPJ binding in human and murine T-lymphoblastic leukemia cells. Proc Natl Acad Sci USA 108:14908–14913

DOI

102
Weber S, Niessen MT, Prox J, Lullmann-Rauch R, Schmitz A (2010) The disintegrin/metalloproteinase Adam10 is essential for epidermal integrity and Notch-mediated signaling. Development 138:495–505

103
Weijzen S, Velders MP, Elmishad AG, Bacon PE, Panella JR (2002) The Notch ligand Jagged-1 is able to induce maturation of monocyte-derived human dendritic cells. J Immunol 169:4273–4278

DOI

104
Wu Y, Cain-Hom C, Choy L, Hagenbeek TJ, deLeon GP(2010) Therapeutic antibody targeting of individual Notch receptors. Nature 464:1052–1057

DOI

105
Xu H, Zhu J, Smith S, Foldi J, Zhao B (2012) Notch-RBP-J signaling regulates the transcription factor IRF8 to promote inflammatory macrophage polarization. Nat Immunol 13:642–650

DOI

106
Xu J, Chi F, Guo T, Punj V, Lee WN (2015) NOTCH reprograms mitochondrial metabolism for proinflammatory macrophage activation. J Clin Invest 125:1579–1590

DOI

107
Yabe Y, Matsumoto T, Tsurumoto T, Shindo H (2005) Immunohistological localization of Notch receptors and their ligands Delta and Jagged in synovial tissues of rheumatoid arthritis. J Orthop Sci 10:589–594

DOI

108
Yamada T, Yamazaki H, Yamane T, Yoshino M, Okuyama H (2003) Regulation of osteoclast development by Notch signaling directed to osteoclastprecursors and through stromal cells. Blood 101:2227–2234

DOI

109
Yashiro-Ohtani Y, Ohtani T, Pear WS (2010) Notch regulation of early thymocyte development. Semin Immunol 22:261–269

DOI

110
Yuan JS, Kousis PC, Suliman S, Visan I, Guidos CJ (2010) Functions of notch signaling in the immune system: consensus and controversies. Annu Rev Immunol 28:343–365

DOI

111
Zanotti S, Canalis E (2010) Notch and the skeleton. Mol Cell Biol 30:886–896

DOI

112
Zeng Q, Li S, Chepeha DB, Giordano TJ, Li J(2005) Crosstalk between tumor and endothelial cells promotes tumor angiogenesis by MAPK activation of Notch signaling. Cancer Cell 8:13–23

DOI

113
Zhang W, Xu W, Xiong S (2010) Blockade of Notch1 signaling alleviates murine lupus via blunting macrophage activation and M2b polarization. J Immunol 184:6465–6478

DOI

114
Zhang Q, Wang C, Liu Z, Liu X, Han C, ., (2012) Notch signal suppresses TLR-triggered inflammatory responses in macrophages by inhibiting ERK1/2-mediated NF-kappaB activation. J Biol Chem 287:6208–6217

DOI

115
Zhao B, Ivashkiv LB (2011) Negative regulation of osteoclastogenesis and bone resorption by cytokines and transcriptional repressors. Arthritis Res Ther 13:234

DOI

116
Zhao B, Zou J, Wang H, Johannsen E, Peng CW (2011) Epstein-Barr virus exploits intrinsic B-lymphocyte transcription programs to achieve immortal cell growth. Proc Natl Acad Sci USA 108:14902–14907

DOI

117
Zhao B, Grimes SN, Li S, Hu X, Ivashkiv LB (2012) TNF-induced osteoclastogenesis and inflammatory bone resorption are inhibitedby transcription factor RBP-J. J Exp Med 209:319–334

DOI

118
Zhou J, Cheng P, Youn JI, Cotter MJ, Gabrilovich DI (2009) Notch and wingless signaling cooperate in regulation of dendritic cell differentiation. Immunity 30:845–859

DOI

Outlines

/