title: IL-8-induced neutrophil chemotaxis is mediated by Janus kinase 3 (JAK3).
abstract: Janus kinase 3 (JAK3) is a non-receptor tyrosine kinase vital to the regulation of T-cells. We report that JAK3 is a mediator of interleukin-8 (IL-8) stimulation of a different class of hematopoietic relevant cells: human neutrophils. IL-8 induced a time- and concentration-dependent activation of JAK3 activity in neutrophils and differentiated HL-60 leukemic cells. JAK3 was more robustly activated by IL-8 than other kinases: p70S6K, mTOR, MAPK or PKC. JAK3 silencing severely inhibited IL-8-mediated chemotaxis. Thus, IL-8 stimulates chemotaxis through a mechanism mediated by JAK3. Further, JAK3 activity and chemotaxis were inhibited by the flavonoid apigenin (4',5,7-trihydroxyflavone) at ∼5nM IC(50). These new findings lay the basis for understanding the molecular mechanism of cell migration as it relates to neutrophil-mediated chronic inflammatory processes.
authors.affiliation: Department of Biochemistry and Molecular Biology, Wright State University School Medicine, Dayton, OH 45435, USA.
authors.forename: Karen M
authors.initials: KM
authors.lastname: Henkels
authors.forename: Kathleen
authors.initials: K
authors.lastname: Frondorf
authors.forename: M Elba
authors.initials: ME
authors.lastname: Gonzalez-Mejia
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Doseff
authors.forename: Julian
authors.initials: J
authors.lastname: Gomez-Cambronero
mesh_terms: D047310:Apigenin / Q000737:chemistry / Q000494:pharmacology; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D016209:Interleukin-8 / Q000494:pharmacology*; D053616:Janus Kinase 3 / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D015394:Molecular Structure; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism; D034622:RNA Interference; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013997:Time Factors
chemical_list: D016209:Interleukin-8; D047310:Apigenin; D053616:Janus Kinase 3; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases