title: The tyrosine kinase BMX is an essential mediator of inflammatory arthritis in a kinase-independent manner.
abstract: Inflammatory cytokines like TNF play a central role in autoimmune disorders such as rheumatoid arthritis. We identified the tyrosine kinase bone marrow kinase on chromosome X (BMX) as an essential component of a shared inflammatory signaling pathway. Transient depletion of BMX strongly reduced secretion of IL-8 in cell lines and primary human cells stimulated by TNF, IL-1β, or TLR agonists. BMX was required for phosphorylation of p38 MAPK and JNK, as well as activation of NF-κB. The following epistasis analysis indicated that BMX acts downstream of or at the same level as the complex TGF-β activated kinase 1 (TAK1)-TAK1 binding protein. At the cellular level, regulation of the IL-8 promoter required the pleckstrin homology domain of BMX, which could be replaced by an ectopic myristylation signal, indicating a requirement for BMX membrane association. In addition, activation of the IL-8 promoter by in vitro BMX overexpression required its catalytic activity. Genetic ablation of BMX conferred protection in the mouse arthritis model of passive K/BxN serum transfer, confirming that BMX is an essential mediator of inflammation in vivo. However, genetic replacement with a catalytically inactive BMX allele was not protective in the same arthritis animal model. We conclude that BMX is an essential component of inflammatory cytokine signaling and that catalytic, as well as noncatalytic functions of BMX are involved.
authors.affiliation: Novartis Institutes for Biomedical Research, CH-4056 Basel, Switzerland.
authors.forename: Marie
authors.initials: M
authors.lastname: Gottar-Guillier
authors.forename: Francis
authors.initials: F
authors.lastname: Dodeller
authors.forename: Dieter
authors.initials: D
authors.lastname: Huesken
authors.forename: Vadim
authors.initials: V
authors.lastname: Iourgenko
authors.forename: Craig
authors.initials: C
authors.lastname: Mickanin
authors.forename: Mark
authors.initials: M
authors.lastname: Labow
authors.forename: Samuel
authors.initials: S
authors.lastname: Gaveriaux
authors.forename: Bernd
authors.initials: B
authors.lastname: Kinzel
authors.forename: Matthias
authors.initials: M
authors.lastname: Mueller
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
authors.forename: Amanda
authors.initials: A
authors.lastname: Littlewood-Evans
authors.forename: Bruno
authors.initials: B
authors.lastname: Cenni
mesh_terms: D000818:Animals; D001168:Arthritis / Q000276:immunology* / Q000378:metabolism; D001798:Blood Proteins; D002460:Cell Line; D004195:Disease Models, Animal; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D053583:Interleukin-1beta / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D010750:Phosphoproteins; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000819:agonists / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D048069:Tumor Necrosis Factors / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D001798:Blood Proteins; D053583:Interleukin-1beta; D016209:Interleukin-8; D048031:JNK Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D010750:Phosphoproteins; D011505:Protein-Tyrosine Kinases; D051193:Toll-Like Receptors; D016212:Transforming Growth Factor beta; D048069:Tumor Necrosis Factors; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7; C039077:platelet protein P47; C492367:BMX protein, human; C492366:Bmx protein, mouse