Abstract
Leukocyte recruitment is considered to playa key role in numerous inflammatory diseases. Tissue accumulation of Jeukocytes is a multi-steps process comprising rolling, adhesion and transmigration. This process depends on the function of several different cells, including leukocytes, endothelial cells, mast cells and macrophages as well as a wide spectrum of inflammatory mediators, such as TNF-alpha and chemokines. Chemokines are effective leukocyte attractants and according to structural properties, chemokines are divided into two major subfamilies, CC and CXC. In general, CC chemokines exert chemotactic influence on monocytes and lymphocytes while CXC chemokine mainly attract neutrophils. However, the mechanisms of chemokine-induced leukocyte recruitment in vivo remain elusive. Mast cells are tissue resident cells exerting multi-functional roles. Upon activation, mast cells release potent mediators, such as histamine, leukotrienes, chemokines and TNF-alpha. The aim of this study was to investigate the role of mast cells in regulating chemokine-provoked tissue infiltration ofleukocytes. It was found that TNF-alpha can activate endothelial cells to express P-selectin and CXC chemokine (MIP-2) and cause leukocyte adhesion in vitro in a glucocorticoid-sensitive manner. Interestingly, chemokines, both MIP-Ialpha, MCP-I and MIP-2, KC, were found to provoke a dose-dependent increase in P-selectin-dependent leukocyte roUing, adhesion and recruitment in vivo. It was demonstrated that chemokine-induced neutrophil recruitment in vivo was abolished in mast cell-deficient mice. TNF-alpha activated endothelial cells (increased E-selectin mRNA expression) in both wild-type and mast cell-deficient animals. In contrast, MIP-Ialpha, MCP-I and MIP-2 increased gene expression of E-selectin only in wild-type mice but not in mast cell-deficient mice, suggesting that chemokine-induced activation of endothelial cells is indeed dependent on mast cells. Moreover, it was observed that mast cell-derived TNF-alpha, but not histamine and leukotrienes, mediated chemokine-induced extravasation ofneutrophils. Considered together, this work elucidates important mechanisms regulating chemokine-induced leukocyte recruitment, which may help understand the pathophysiology of inflammatory diseases and serve as a basis for development of anti-inflammatory treatment strategies.
Original language | English |
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Qualification | Doctor |
Awarding Institution |
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Supervisors/Advisors |
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Award date | 2006 Oct 26 |
Publisher | |
ISBN (Print) | 91-85559-37-7 |
Publication status | Published - 2006 |
Bibliographical note
Defence detailsDate: 2006-10-26
Time: 13:00
Place: CRC, Clinical Research Centre, Public Forum, Entrance 72, Malmö University Hospital, Malmö, Sweden
External reviewer(s)
Name: Söderholm, Johan D
Title: Associate professor, MD, PhD
Affiliation: Linköping University
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<div class="article_info">Qing Liu, Yusheng Wang and Henrik Thorlacius. <span class="article_issue_date">2000</span>. <span class="article_title">Dexamethasone inhibits tumor necrosis factor-?-induced expression of macro-phage inflammatory protein-2 and adhesion of neutrophils to endothelial cells.</span> <span class="journal_series_title">Biochemical and Biophysical Research Communications</span>, <span class="journal_volume">vol 271</span> <span class="journal_pages">pp 364-367</span>. <span class="journal_distributor">Department of Surgery, Malmö University Hospital, Lund University, 205 02 Malmö, Sweden</span></div>
<div class="article_info">Xiao Wei Zhang, Qing Liu, Yusheng Wang and Henrik Thorlacius. <span class="article_issue_date">2001</span>. <span class="article_title">CXC chemokines, MIP-2 and KC, induce P-selectin-dependent neutrophil rolling and extravascular migration in vivo.</span> <span class="journal_series_title">British Journal of Pharmacology</span>, <span class="journal_volume">vol 133</span> <span class="journal_pages">pp 413-421</span>. <span class="journal_distributor">Department of Surgery, Malmö Unviersity Hospital, Lund University, 205 02 Malmö, Sweden</span></div>
<div class="article_info">Ming Xiu Wan, Yusheng Wang, Qing Liu, Rene Schramm and Henrik Thorlacius. <span class="article_issue_date">2003</span>. <span class="article_title">CC chemokines induce P-selectin-dependent neutrophil rolling and recruitment in vivo: intermediary role of mast cells.</span> <span class="journal_series_title">British Journal of Pharmacology</span>, <span class="journal_volume">vol 138</span> <span class="journal_pages">pp 698-706</span>. <span class="journal_distributor">Department of Surgery, Malmö Univeristy Hospital, Lund University, 20502 Malmö, Sweden</span></div>
<div class="article_info">Yusheng Wang and Henrik Thorlacius. <span class="article_issue_date">2005</span>. <span class="article_title">Mast cell-derived tumor necrosis factor-? mediates macrophage inflammatory protein-2-induced recruitment of neutrophils in mice.</span> <span class="journal_series_title">British Journal of Pharmacology</span>, <span class="journal_volume">vol 145</span> <span class="journal_pages">pp 1062-1068</span>. <span class="journal_distributor">Department of Surgery, Malmö University Hospital, Lund University, 20502 Malmö, Sweden</span></div>
Subject classification (UKÄ)
- Surgery
Free keywords
- chemokines
- mast cells
- TNF-alpha
- dexamethasone
- P-selectin
- E-selectin
- activation
- Medicine (human and vertebrates)
- endothelial cells
- adhesion
- Neutrophil
- Medicin (människa och djur)
- recruitment