title: Mast cell-derived tumour necrosis factor-alpha mediates macrophage inflammatory protein-2-induced recruitment of neutrophils in mice.
abstract: Recent studies have indicated that mast cells play an intermediate role in chemokine-induced neutrophil recruitment in vivo. The aim of the present investigation was to determine the role of tumour necrosis factor-alpha (TNF-alpha) in neutrophil recruitment provoked by the CXC chemokine macrophage inflammatory protein-2 (MIP-2). For this purpose, we used mast cell- and TNF-alpha-deficient mice and studied neutrophil adhesion to endothelial cells in vitro and neutrophil recruitment in the mouse cremaster muscle in vivo. In contrast to the classical chemoattractant formyl-methionine-leucine-phenylalanin (fMLP), MIP-2 dose dependently increased neutrophil accumulation in vivo. This MIP-2-regulated neutrophil recruitment was abolished in mast cell-deficient mice. TNF-alpha increased E-selectin mRNA expression in both wild-type (WT) and mast cell-deficient mice. In contrast, MIP-2 challenge increased gene expression of E-selectin in WT but not in mast cell-deficient animals. Moreover, MIP-2-provoked extravascular accumulation of neutrophils was reduced by 78% in mice lacking TNF-alpha. In order to better define the role of mast cell-derived TNF-alpha in neutrophil responses to MIP-2, we used an in vitro endothelial cell adhesion assay with and without mast cells. Interestingly, MIP-2-induced neutrophil adhesion to endothelial cells was decreased by 58% using TNF-alpha-deficient compared to WT mast cells. Moreover, mast cell secretion of TNF-alpha increased by more than 71% in response to challenge with MIP-2. Taken together, our results suggest that MIP-2-induced neutrophil recruitment is mediated by TNF-alpha released from local mast cells. These findings help to explain the complex molecular interactions between chemokines, mast cell activation and neutrophil infiltration in vivo.
authors.affiliation: Department of Surgery, Malmö University Hospital, Lund University, S-205 02 Malmö, Sweden.
authors.forename: Yusheng
authors.initials: Y
authors.lastname: Wang
authors.forename: Henrik
authors.initials: H
authors.lastname: Thorlacius
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D054426:Chemokine CXCL2; D018925:Chemokines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019040:E-Selectin / Q000096:biosynthesis; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D008297:Male; D008407:Mast Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D020556:Neutrophil Infiltration / Q000187:drug effects*; D009504:Neutrophils / Q000166:cytology* / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis; D023063:Receptors, Interleukin-8B / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000502:physiology*
chemical_list: D054426:Chemokine CXCL2; D018925:Chemokines; C404915:Cxcl2 protein, mouse; D019040:E-Selectin; D012333:RNA, Messenger; D023063:Receptors, Interleukin-8B; D014409:Tumor Necrosis Factor-alpha