Bruton’s tyrosine kinase is not essential for LPS-induced activation of human monocytes - 20/08/11
, Eduardo López-Granados, MD, PhD a, Maite Pozo, PhD b, Cristina Rodríguez, PhD b, Prado Sabina, PhD a, Antonio Ferreira, MD, PhD a, Gumersindo Fontan, MD, PhD a, Maria Cruz García-Rodríguez, MD, PhD a, Susana Alemany, MD, PhD b
Reprint requests: Rebeca Pérez de Diego, PhD, Po Castellana, 261, Immunology Unit, University Hospital La Paz, 28046 Madrid, Spain.Madrid, Spain
Abstract |
Background |
X-linked agammaglobulinemia (XLA) is characterized by impaired B-cell differentiation caused by mutations in the Bruton’s tyrosine kinase (Btk) gene. The natural disease model, the X-linked immunodeficiency mouse, shows a less severe phenotype, indicating a different requirement of Btk in human and mouse B cells. Btk is also expressed in the myeloid line and participates in LPS signaling. Deficient oxidative burst and myeloid differentiation have been reported in the X-linked immunodeficiency mouse, but the precise mechanism and relevance of Btk activity in human monocytes is poorly understood.
Objective |
The apparent absence in XLA of clinical manifestations of myeloid deficiency prompted us to explore the relevance of complete Btk absence in human myeloid cells.
Methods |
Seven patients with XLA with BTK mutations conditioning a null protein expression were included in the study. Monocyte LPS-induced mitogen-activated protein kinase activation, TNF-⍺ and IL-6 production in monocytes, and oxidative burst in monocytes and granulocytes were analyzed by means of flow cytometry.
Results |
We show that in response to LPS, Btk-null monocytes from patients with XLA induce early mitogen-activated protein kinase activation and intracellular TNF-⍺ and IL-6 production with the same intensity as cells from age- and sex-matched control subjects. In addition, the oxidative burst in response to LPS and other stimulants was completely normal in Btk-null monocytes and neutrophils.
Conclusion |
Our results indicate that Btk is not essential for early LPS signaling in human monocytes and that different Btk dependency might exist between human and mouse myeloid cells.
Clinical implications |
These findings provide a better understanding of XLA, and they show the differences between human XLA and murine Xid models.
Le texte complet de cet article est disponible en PDF.Key words : X-linked agammaglobulinemia, Bruton’s tyrosine kinase, LPS signaling, mitogen-activated protein kinases, tumor necrosis factor ⍺, IL-6, oxidative burst activity, monocytes
Abbreviations used : BCR, Btk, DC, Erk, FITC, IRAK, JNK, MAP kinase, PMA, PR, ROI, TLR4, Xid, XLA
Plan
| This work was supported by “Fondo de Investigación Sanitaria (FIS)” grant no. 020982, by the CICYT (BMC2002-00437), and by AICR and Fundación “La Caixa.” RPdD is the recipient of a fellowship from the FIS, CR from the ME, and MP from the AICR. Disclosure of potential conflict of interest: The authors have declared they have no conflict of interest. |
Vol 117 - N° 6
P. 1462-1469 - juin 2006 Retour au numéro
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