The vagus nerve as a modulator of intestinal inflammation - TI Pharma

More documents

Recommendations

Info

Chapter 4 nicotinic reduction of TNF activation does not depend on STAT3 phosphorylation, since nicotine still reduces TNF production in STAT3F transfected cells. In contrast, transfection with STAT3D does prevent the anti-inflammatory potential of nicotine. In STAT3D macrophages, glutamic residues 434 and 435 are replaced by alanine, that way inhibiting the DNA-binding activity of STAT by making dimers unable to bind the target DNA 19 , while tyrosine phosphorylation and dimerization are allowed. This suggests that nicotinic inhibition of the inflammatory response is dependent on STAT3 DNA binding. However, we clearly showed that nicotine inhibits p65 translocation to the nucleus (Fig. 4B), which makes it more likely that STAT3 exerts its effect in the cytosol, rather than in the nucleus. Moreover, our results indicate that pharmacological inhibition of STAT3 prevents the activation of the p65RelA/p50NFkB pathway without affecting the other NF-kB proteins including RelB, c-Rel and p52NF-kB2. In normal conditions, after JAK2 phoshporylates STAT3, it dimerizes and translocates into the nucleus. Together, our data indicate a role for unphosphorylated STAT3 (U-STAT) in mediating the anti-inflammatory effect of nicotine. In conjunction with this hypothesis, inhibition of STAT3 tyrosine phosporylation by using STAT3F constructs can lead to higher levels of unphosphorylated U-STAT3. Recent studies indicate that U-STAT3 can bind to NF-κB in competition with IκBα, ultimately resulting in reduced NF-kB transactivation and cytokine production 20 . This mechanism is completely abolished with inhibition of STAT3 expression leading to the enhanced activation of NF-κB observed in STAT3-knockout mice. Additional work is required to further explore this role of USTAT3 in the cholinergic antiinflammatory response. Identification of intracellular signaling pathways involved in mediating the antiinflammatory effect of cholinergic agonists is important to specifically target the pathway and avoid toxic side effects. Our results confirm that JAK2-STAT3 signaling is required for nicotine induced reduction in NF-kB activation and cytokine production in peritoneal macrophages. However, STAT3 phosphorylation seems to be of less significance in this process than previously thought. Furthermore, our results suggest that targeting JAK2-STAT3 signaling may provide pharmacologic advantages for the treatment of inflammatory disorders. However, the JAK2-STAT3 signaling pathway is a complex system which can act both pro-and anti-inflammatory, is tightly regulated and not fully understood yet 9 . Characteristic examples of different responses are the differential expression of STAT3 isoforms in different cell types. Therefore, further examination is needed to establish the potential of targeting JAK2-STAT3 in restraining inflammation. 74
REFERENCES Deciphering STAT3 signaling in cholinergic immune-modulation 1. Borovikova LV, Ivanova S, Zhang M et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 2000;405:458-62. 2. De Jonge WJ, van der Zanden EP, The FO et al. Stimulation of the vagus nerve attenuates macrophage activation by activating the Jak2-STAT3 signaling pathway. Nat Immunol 2005;6:844-51. 3. Ghia JE, Blennerhassett P, Kumar-Ondiveeran H, Verdu EF, Collins SM. The vagus nerve: a tonic inhibitory influence associated with inflammatory bowel disease in a murine model. Gastroenterology 2006;131:1122-30. 4. van Westerloo DJ, Giebelen IA, Florquin S et al. The vagus nerve and nicotinic receptors modulate experimental pancreatitis severity in mice. Gastroenterology 2006;130:1822-30. 5. van Maanen MA, Lebre MC, van der PT et al. Stimulation of nicotinic acetylcholine receptors attenuates collagen-induced arthritis in mice. Arthritis Rheum 2009;60:114-22. 6. van der Zanden EP, Snoek SA, Heinsbroek SE et al. Vagus nerve activity augments intestinal macrophage phagocytosis via nicotinic acetylcholine receptor alpha4beta2. Gastroenterology 2009;137:1029-39, 1039. 7. van der Zanden EP, Boeckxstaens GE, De Jonge WJ. The vagus nerve as a modulator of intestinal inflammation. Neurogastroenterol Motil 2009;21:6-17. 8. De Jonge WJ, van der Zanden EP, The FO et al. Stimulation of the vagus nerve attenuates macrophage activation by activating the Jak2-STAT3 signaling pathway. Nat Immunol 2005;6:844-51. 9. Takeda K, Clausen BE, Kaisho T et al. Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils. Immunity 1999;10:39-49. 10. Murray PJ. The JAK-STAT signaling pathway: input and output integration. J Immunol 2007;178:2623-29. 11. Kubo M, Hanada T, Yoshimura A. Suppressors of cytokine signaling and immunity. Nat Immunol 2003;4:1169-76. 12. Levy DE, Lee CK. What does Stat3 do? J Clin Invest 2002;109:1143-48. 13. Welte T, Zhang SS, Wang T et al. STAT3 deletion during hematopoiesis causes Crohn‘s disease-like pathogenesis and lethality: a critical role of STAT3 in innate immunity. Proc Natl Acad Sci U S A 2003;100:1879-84. 14. Schust J, Sperl B, Hollis A, Mayer TU, Berg T. Stattic: a small-molecule inhibitor of STAT3 activation and dimerization. Chem Biol 2006;13:1235-42. 15. Hui L, Yao Y, Wang S et al. Inhibition of Janus kinase 2 and signal transduction and activator of transcription 3 protect against cecal ligation and puncture-induced multiple organ damage and mortality. J Trauma 2009;66:859-65. 16. de Koning JP, Soede-Bobok AA, Ward AC et al. STAT3-mediated differentiation and survival and of myeloid cells in response to granulocyte colony-stimulating factor: role for the cyclin-dependent kinase inhibitor p27(Kip1). Oncogene 2000;19:3290-3298. 17. Matsukawa A, Takeda K, Kudo S, Maeda T, Kagayama M, Akira S. Aberrant inflammation and lethality to septic peritonitis in mice lacking STAT3 in macrophages and neutrophils. J Immunol 2003;171:6198-205. 18. Kirken RA, Erwin RA, Taub D et al. Tyrphostin AG-490 inhibits cytokine-mediated JAK3/STAT5a/b signal transduction and cellular proliferation of antigen-activated human T cells. J Leukoc Biol 1999;65:891-99. 19. Nakajima K, Yamanaka Y, Nakae K et al. A central role for Stat3 in IL-6-induced regulation of growth and differentiation in M1 leukemia cells. EMBO J 1996;15:3651-58. 20. Yang J, Liao X, Agarwal MK, Barnes L, Auron PE, Stark GR. Unphosphorylated STAT3 accumulates in response to IL-6 and activates transcription by binding to NFkappaB. Genes Dev 2007;21:1396-408. 75
Page 1 and 2:
The vagus nerve as a modulator ofin
Page 3 and 4:
The vagus nerve as a modulator of i
Page 5 and 6:
Promotiecommissie Promotores: Prof.
Page 7 and 8:
Table of contents Chapter 1 Introdu
Page 9 and 10:
Introduction and outline The aim of
Page 11 and 12:
Introduction and outline Hence, the
Page 13 and 14:
Introduction and outline 18. van de
Page 15 and 16:
Chapter 2 ABSTRACT The cholinergic
Page 17 and 18:
Chapter 2 neurotransmitter ACh with
Page 19 and 20: Chapter 2 THE VAGUS NERVE AND CHOLI
Page 21 and 22: Chapter 2 nicotine treatment impair
Page 23 and 24: Chapter 2 Figure 1. Hypothetical sc
Page 25 and 26: Chapter 2 unclear whether this hybr
Page 27 and 28: Chapter 2 reduction of NF-κB activ
Page 29 and 30: Chapter 2 CONCLUDING REMARKS The hy
Page 31 and 32: Chapter 2 34 17. The FO, Boeckxstae
Page 33 and 34: Chapter 2 55. Moser N, Mechawar N,
Page 35 and 36: Chapter 2 93. Shafique S, Dalsing M
Page 37 and 38: Chapter 3 ABSTRACT Acetylcholine re
Page 39 and 40: Chapter 3 by bowel manipulation 12
Page 41 and 42: Chapter 3 for preparation of whole
Page 43 and 44: Chapter 3 Figure 1. Nicotine attenu
Page 45 and 46: Chapter 3 Figure 2. Inhibition of m
Page 47 and 48: Chapter 3 macrophage cell lysates s
Page 49 and 50: Chapter 3 reports 2 . We next incub
Page 51 and 52: Chapter 3 Figure 5. Perioperative e
Page 53 and 54: Chapter 3 Figure 7. Stimulation of
Page 55 and 56: Chapter 3 Activation of the STAT3 c
Page 57 and 58: Chapter 3 REFERENCE LIST 60 1. Trac
Page 59 and 60: 4 CHAPTER Deciphering STAT3 signali
Page 61 and 62: INTRODUCTION Deciphering STAT3 sign
Page 63 and 64: Deciphering STAT3 signaling in chol
Page 69: DISCUSSION Deciphering STAT3 signal
Page 73 and 74: Chapter 5 ABSTRACT Background and A
Page 75 and 76: Chapter 5 METHODS Reagents and anti
Page 77 and 78: Chapter 5 described previously 6 .
Page 79 and 80: Chapter 5 Figure 1 Cholinergic agon
Page 81 and 82: Chapter 5 Figure 3 Cholinergic agon
Page 83 and 84: Chapter 5 we analyzed whether nicot
Page 85 and 86: Chapter 5 Zymosan induced formation
Page 87 and 88: Chapter 5 marker CD11 c (Fig. 7E),
Page 89 and 90: Chapter 5 Our data demonstrate that
Page 91 and 92: Chapter 5 REFERENCE LIST 96 1. Boro
Page 93 and 94: Thesis E.P.M. van der Zanden The va
Page 95 and 96: Summary and conclusions The goal of
Page 97 and 98: Summary and conclusions whether the
Page 99 and 100: Summary and conclusions exposure co
Page 101 and 102: REFERENCE LIST Summary and conclusi
Page 103 and 104: Nederlandse samenvatting
Page 105 and 106: Chapter 7 van STAT3 in de ‘cholin
Page 107 and 108: Chapter 7 De bevinding dat nicotine
Page 109 and 110: Chapter 7 macrofagen aan te tonen (
Page 111 and 112: Chapter 7 18. Yu Z, Zhang W, Kone B
Page 113 and 114: Shizuo Akira Department of Host Def
Page 115 and 116: List of publications
Page 117 and 118: Dankwoord
Page 119 and 120: om de ene keer olijfolie te drinken
Page 121:
Curriculum Vitae Curriculum Vitae E
show all

The vagus nerve as a modulator of intestinal inflammation - TI Pharma

Create successful ePaper yourself

Delete template?

Save as template?