Toll-like receptor 4–, 7–, and 8–activated myeloid cells from patients with X-linked agammaglobulinemia produce enhanced inflammatory cytokines - 24/12/11
Corresponding author: Charlotte Cunningham-Rundles, MD, PhD, Departments of Medicine and Pediatrics, the Immunology Institute, Mount Sinai School of Medicine, 1425 Madison Ave, New York, NY 10029.Abstract |
Background |
Bruton tyrosine kinase (BTK) is a component of signaling pathways downstream from Toll-like receptors (TLRs) 2, 4, 7, 8, and 9. Previous work in BTK-deficient mice, cell lines, and cultured cells from patients with X-linked agammaglobulinemia (XLA) suggested defective TLR-driven cytokine production.
Objective |
We sought to compare TLR-4–, TLR-7–, and TLR-8–induced cytokine production of primary cells from patients with XLA with that seen in control cells.
Methods |
PBMCs from patients with XLA, freshly isolated plasmacytoid dendritic cells, monocytes, and monocytoid dendritic cells were activated with TLR-4, TLR-7, and TLR-8 agonists. Signaling intermediates and intracellular and secreted cytokine levels were compared with those seen in control cells.
Results |
Although TLR-4, TLR-7, and TLR-8 activation of nuclear factor κB and mitogen-activated protein kinase pathways in cells from patients with XLA and control cells were comparable, TLR-activated freshly isolated monocytes and monocytoid dendritic cells from patients with XLA produced significantly more TNF-⍺, IL-6, and IL-10 than control cells. TLR-7/8–activated plasmacytoid dendritic cells produced normal amounts of IFN-⍺. In murine models BTK regulates the degradation of Toll–IL-1 receptor domain–containing adaptor protein, terminating TLR-4–induced cytokine production. Although this might explain the heightened TLR-4–driven cytokine production we observed, Toll–IL-1 receptor domain–containing adaptor protein degradation is intact in cells from patients with XLA, excluding this explanation.
Conclusion |
In contrast to previous studies with BTK-deficient mice, cell lines, and cultured cells from patients with XLA suggesting impaired TLR-driven cytokine production, these data suggest that BTK inhibits TLR-induced cytokine production in primary human cells.
Le texte complet de cet article est disponible en PDF.Key words : Bruton tyrosine kinase, X-linked agammaglobulinemia, Toll-like receptors, MyD88 adapter-like protein, Toll–IL-1 receptor domain–containing adapter protein
Abbreviations used : BTK, CVID, ERK, IRAK, JNK, MAPK, mDC, NF-κB, pDC, TIRAP, TLR, XLA
Plan
| Supported by National Institutes of Health grants AI 101093, AI-467320, and AI-48693; National Institute of Allergy and Infectious Diseases contract no. 03-22, the Jeffrey Modell Foundation, and the David S. Gottesman Immunology Chair. |
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| Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. |
Vol 129 - N° 1
P. 184 - janvier 2012 Retour au numéro
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