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Published online before print November 11, 2004

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(Journal of Leukocyte Biology. 2005;77:159-165.)
© 2005 by Society for Leukocyte Biology

Blockade of ₆ integrin inhibits IL-1ß- but not TNF--induced neutrophil transmigration in vivo

Cardiovascular Medicine Unit, Eric Bywaters Centre for Vascular Inflammation, Faculty of Medicine, Imperial College London, Hammersmith Hospital, United Kingdom

¹ Correspondence: Cardiovascular Medicine Unit, The Eric Bywaters Centre for Vascular Inflammation, Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK. E-mail: s.nourshargh{at}imperial.ac.uk

In vitro and in vivo evidence supports a functional role for the integrin ₆ß₁ 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 ₆ß₁ 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 ₆ß₁ exhibited a similar profile of stimulus specificity in this context. The cytokines interleukin-1ß (IL-1ß) and tumor necrosis factor (TNF-) 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 ₆ß₁ was investigated using an ₆ integrin-blocking monoclonal antibody GoH3. In both models, GoH3 significantly inhibited neutrophil transmigration induced by IL-1ß but not TNF-. This cytokine-specific role of ₆ integrin was associated with enhanced cell-surface expression of ₆ß₁ on transmigrated neutrophils (as compared with blood cells) in response to IL-1ß but not TNF-. Using lipopolysaccharide as an inflammatory stimulus in the cremaster muscle model, the study also provides evidence for the involvement of ₆ integrin in leukocyte transmigration as mediated by endogenously generated IL-1ß. Collectively, the findings demonstrate that ₆ß₁ blockade inhibits neutrophil migration induced by exogenous and endogenous IL-1ß but not TNF-, observations that are associated with increased expression of the integrin on transmigrated leukocytes.

Key Words: inflammation • cytokine • leukocyte • adhesion molecules

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