title: Blockade of alpha6 integrin inhibits IL-1beta- but not TNF-alpha-induced neutrophil transmigration in vivo.
abstract: In vitro and in vivo evidence supports a functional role for the integrin alpha6beta1 in neutrophil migration through the perivascular basement membrane, a response that in vivo appears to be associated with platelet/endothelial cell adhesion molecule-1 (PECAM-1)-mediated up-regulation of alpha6beta1 on the cell surface of transmigrating leukocytes. As the involvement of PECAM-1 in leukocyte migration is cytokine-specific, the aim of the present study was to investigate whether alpha6beta1 exhibited a similar profile of stimulus specificity in this context. The cytokines interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha) were used to elicit neutrophil migration in two murine models of inflammation, migration through cremasteric venules, as observed by intravital microscopy, and migration into the peritoneal cavity. The role of alpha6beta1 was investigated using an alpha6 integrin-blocking monoclonal antibody GoH3. In both models, GoH3 significantly inhibited neutrophil transmigration induced by IL-1beta but not TNF-alpha. This cytokine-specific role of alpha6 integrin was associated with enhanced cell-surface expression of alpha6beta1 on transmigrated neutrophils (as compared with blood cells) in response to IL-1beta but not TNF-alpha. Using lipopolysaccharide as an inflammatory stimulus in the cremaster muscle model, the study also provides evidence for the involvement of alpha6 integrin in leukocyte transmigration as mediated by endogenously generated IL-1beta. Collectively, the findings demonstrate that alpha6beta1 blockade inhibits neutrophil migration induced by exogenous and endogenous IL-1beta but not TNF-alpha, observations that are associated with increased expression of the integrin on transmigrated leukocytes.
authors.affiliation: Cardiovascular Medicine Unit, Eric Bywaters Centre for Vascular Inflammation, Faculty of Medicine, Imperial College London, Hammersmith Hospital, United Kingdom.
authors.forename: John P
authors.initials: JP
authors.lastname: Dangerfield
authors.forename: Shijun
authors.initials: S
authors.lastname: Wang
authors.forename: Sussan
authors.initials: S
authors.lastname: Nourshargh
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D039503:Integrin alpha6 / Q000096:biosynthesis / Q000187:drug effects* / Q000502:physiology; D039121:Integrin alpha6beta1 / Q000037:antagonists & inhibitors / Q000502:physiology; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D007962:Leukocytes / Q000187:drug effects / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000502:physiology*; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000911:Antibodies, Monoclonal; D039503:Integrin alpha6; D039121:Integrin alpha6beta1; D007375:Interleukin-1; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha