Toll-like receptor 4-, 7-, and 8-activated myeloid cells from patients with X-linked agammaglobulinemia produce enhanced inflammatory cytokines

Thomas U. Marron, Monica Martinez-Gallo, Joyce E. Yu, Charlotte Cunningham-Rundles*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

35 Citations (Scopus)

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-α, IL-6, and IL-10 than control cells. TLR-7/8-activated plasmacytoid dendritic cells produced normal amounts of IFN-α. 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.

Original languageEnglish
Pages (from-to)184-190.e4
JournalJournal of Allergy and Clinical Immunology
Volume129
Issue number1
DOIs
Publication statusPublished - Jan 2012

Keywords

  • Bruton tyrosine kinase
  • MyD88 adapter-like protein
  • Toll-IL-1 receptor domain-containing adapter protein
  • Toll-like receptors
  • X-linked agammaglobulinemia

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