title: Role of c-Abl in L-selectin shedding from the neutrophil surface.
abstract: L-selectin is a key molecule that participates in neutrophil tethering and subsequent rolling. It is cleaved from the surface of neutrophils activated in the presence of lipopolysaccharides, N-formyl-methionine-leucine-phenylalanine (fMLP), or Interleukin-8 (IL-8). We previously showed that L-selectin is also shed from the neutrophil surface during rolling on sialyl Lewis-x coated surfaces in a force-, ADAM-17 sheddase-, and p38 MAP kinase-dependent manner under flow. c-Abl tyrosine kinase is phosphorylated when L-selectin on the surface of neutrophils is cross-linked with anti-L-selectin antibodies. Here, we study the effect of c-Abl inhibition on L-selectin shedding from primary human neutrophils in static conditions following exposure to fMLP, IL-8, and hypotonic buffer and under flow through sialyl Lewis-x coated microtubes. Results indicate that c-Abl inhibition by STI571 significantly affects neutrophil adhesion via L-selectin, by decreasing the average rolling velocity and increasing the flux of rolling cells. The change in surface receptor expression was verified by flow cytometry. Interestingly, other forms of L-selectin shedding induced by fMLP, IL-8 or osmotic swelling were unaffected by STI571 treatment. These findings implicate the c-Abl signaling molecule in regulating L-selectin mechanical shedding in response to shear stress, setting this type of signaling apart from those triggered by the presence of a hypotonic environment, fMLP, or IL-8. This study sheds light on the role of c-Abl in neutrophil adhesion not previously reported in the literature.
authors.affiliation: Department of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Carissa J
authors.initials: CJ
authors.lastname: Ball
authors.forename: Michael R
authors.initials: MR
authors.lastname: King
mesh_terms: D001549:Benzamides; D006801:Humans; D000068877:Imatinib Mesylate; D039641:Integrin beta Chains / Q000378:metabolism; D016209:Interleukin-8 / Q000494:pharmacology; D019041:L-Selectin / Q000378:metabolism*; D036904:Leukocyte Rolling; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction; D013314:Stress, Mechanical
chemical_list: D001549:Benzamides; D039641:Integrin beta Chains; D016209:Interleukin-8; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D019041:L-Selectin; D000068877:Imatinib Mesylate; D016315:Proto-Oncogene Proteins c-abl