Stem cell factor-mediated activation pathways promote murine eosinophil CCL6 production and survival.
Eosinophil activation during allergic diseases has a detrimental role in the generation of pathophysiologic responses. Stem cell factor (SCF) has recently shown an inflammatory, gene-activating role on eosinophils and contributes to the generation of pathophysiologic changes in the airways during allergic responses. The data in the present study outline the signal transduction events that are induced by SCF in eosinophils and further demonstrate that MEK-mediated signaling pathways are crucial for SCF-induced CCL6 chemokine activation and eosinophil survival. SCF-mediated eosinophil activation was demonstrated to include PI-3K activation as well as MEK/MAPK phosphorylation pathways. Subsequent analysis of CCL6 gene activation and production induced by SCF in the presence or absence of rather specific inhibitors for certain pathways demonstrated that the MEK/MAPK pathway but not the PI-3K pathway was crucial for the SCF-induced CCL6 gene activation. These same signaling pathways were shown to initiate antiapoptotic events and promote eosinophil survival, including up-regulation of BCL2 and BCL3. Altogether, SCF appears to be a potent eosinophil activation and survival factor.
Dolgachev
Vladislav
V
Department of Pathology, University of Michigan Medical School, 109 Zina Pitcher Place, Room 4618, Ann Arbor, MI 48109-2200, USA. vdolgach@umich.edu
Thomas
Molly
M
Berlin
Aaron
A
Lukacs
Nicholas W
NW
D000818:Animals; D017209:Apoptosis; D002070:Butadienes / Q000494:pharmacology; D002470:Cell Survival; D002478:Cells, Cultured; D019742:Chemokines, CC / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004804:Eosinophils / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D051379:Mice; D009570:Nitriles / Q000494:pharmacology; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000494:pharmacology*
D002070:Butadienes; D019742:Chemokines, CC; D004791:Enzyme Inhibitors; D009570:Nitriles; D019089:Stem Cell Factor; C113580:U 0126; C070959:Ccl6 protein, mouse; D048369:MAP Kinase Kinase 1