Abstract
The entry of neutrophils into tissue has been well characterised; however the fate of these cells once inside the tissue microenvironment is not fully understood. A variety of signal transduction pathways including those involving class I PI3 Kinases have been suggested to be involved in neutrophil migration. This study aims to determine the involvement of PI3 Kinases in chemokinetic and chemotactic neutrophil migration in response to CXCL8 and GM-CSF in a three-dimensional collagen gel, as a model of tissue. Using a three-dimensional collagen assay chemokinetic and chemotactic migration induced by CXCL8 was inhibited with the pan PI3 Kinase inhibitor wortmannin. Analysis of the specific Class I PI3 Kinase catalytic isoforms alpha, delta and gamma using the inhibitors PIK-75, PIK-294 and AS-605240 respectively indicated differential roles in CXCL8-induced neutrophil migration. PIK-294 inhibited both chemokinetic and chemotactic CXCL8-induced migration. AS-605240 markedly reduced CXCL8 induced chemokinetic migration but had no effect on CXCL8 induced chemotactic migration. In contrast PIK-75 inhibited chemotactic migration but not chemokinetic migration. At optimal concentrations of GM-CSF the inhibitors had no effect on the percentage of neutrophil migration in comparison to the control however at suboptimal concentrations wortmannin, AS-605240 and PIK-294 inhibited chemokinesis. This study suggests that PI3 Kinase is necessary for CXCL8 induced migration in a 3D tissue environment but that chemokinetic and chemotactic migration may be controlled by different isoforms with gamma shown to be important in chemokinesis and alpha important in chemotaxis. Neutrophil migration in response to suboptimal concentrations of GM-CSF is dependent on PI3 Kinase, particularly the gamma and delta catalytic isoforms.
Highlights
Neutrophil accumulation in the tissue plays an important role in host defence to a wide range of infections
This study suggests that PI3 Kinase is necessary for CXCL8 induced migration in a 3D tissue environment but that chemokinetic and chemotactic migration may be controlled by different isoforms with gamma shown to be important in chemokinesis and alpha important in chemotaxis
To determine the normal migration pattern of neutrophils in a 3D environment, we stimulated the neutrophils with GM-CSF and CXCL8 in a dose-dependent manner
Summary
Neutrophil accumulation in the tissue plays an important role in host defence to a wide range of infections. In chronic inflammatory diseases neutrophil accumulation within tissue can be detrimental. An understanding of the signal transduction pathways controlling the migration of neutrophils within the lung could prove beneficial in the treatment of inflammatory diseases. There are three main forms of leucocyte migration, random, chemokinesis and chemotaxis. Both random and chemokinesis are non-directional motions the difference being that chemokinesis occurs in the presence of a (usually chemical), stimuli and random motion occurs in the absence of such stimuli. Chemotaxis is induced in response to a chemical stimulus, usually a chemoattractant but unlike chemokinesis the migration is directed towards the source of the stimulus [4]
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