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19 STIMULUS SPECIFIC ROLE FOR FER TYROSINE KINASE IN NEUTROPHIL RECRUITMENT: ROLE OF p38 MAPK AND PI3 KINASE M Khajah, G Andonegui, D-M McCafferty Neutrophil recruitment and directional movement toward chemotactic stimuli are important processes in the innate immune response. This study examines if Fer PTK plays a role in neutrophil recruitment and chemotaxis to various stimuli in vivo and in vitro.
Gastrointestinal Research Group, University of Calgary, Calgary, Alberta
Mice targeted with a kinase-inactivating mutation (FERDR/DR) or wild types (WT) were used. In vivo time-lapse intravital microscopy was used to examine leukocyte recruitment and chemotaxis in response to keratinocyte-derived cytokine (KC; 5.2 µM) or chemotactic peptide WKYMVm (0.1 µM). In WT and FERDR/DR no difference in chemotaxis in response to KC was observed. However, in response to WKYMVm a twofold increase in leukocyte emigration was noted in FERDR/DR mice (P<0.05). Bone marrow chimeras, where FERDR/DR received WT bone marrow, showed similar chemotaxis to WT in response to WKYMVm suggesting that endothelial Fer kinase was not playing a role in chemotaxis.
In vitro neutrophil chemotaxis was assessed with bone marrow derived neutrophils using an under agarose gel assay. No difference in chemotaxis was noted between WT and FERDR/DR mice in response to KC in vitro. However, a twofold increase in chemotaxis was noted in FERDR/DR vs WT neutrophils in response to WKYMVm. This chemotactic response was inhibited by two p38 MAPK inhibitors (SKF86002 and SB203580) in WT mice but not in FERDR/DR mice suggesting a regulatory role for Fer kinase on the p38 MAPK pathway. Interestingly, in FERDR/DR mice a role for the PI3 kinase pathway in chemotaxis was revealed using a PI3 kinase inhibitor (LY294002).
These data suggest that Fer kinase regulates neutrophil chemotaxis in response to WKYMVm through the regulation of p38 MAPK signalling pathway.
This work is funded by a Canadian Institutes of Health Research operating grant