Distinct roles of Ca2+ mobilization and G protein usage on regulation of Toll-like receptor function in human and murine mast cells

Asifa K. Zaidi, Elden Retna Raj B Thangam, Hydar Ali

Research output: Contribution to journalArticle

Abstract

Toll-like receptors (TLRs) expressed in mast cells play important roles in orchestrating host defence against bacterial pathogens. Previous studies demonstrated that TLR2 agonist tripalmitoyl-S-glycero-Cys-(Lys)4 (Pam3Cys) stimulates both degranulation and cytokine production in human mast cells but only induces cytokine production in murine mast cells. To determine the molecular basis for this difference, we utilized a human mast cell line LAD 2, murine lung and bone marrow-derived mast cells (MLMC and BMMC). We found that Pam3Cys caused a sustained Ca2+ mobilization and degranulation in LAD 2 mast cells but not in MLMC or BMMC. Despite these differences, Pam3Cys stimulated equivalent chemokine CCL2 generation in all mast cell types tested. Cyclosporin A (CsA), an inhibitor of Ca 2+/calcineurin-mediated nuclear factor of activated T cells (NFAT) activation, blocked chemokine production in LAD 2 but not in MLMC or BMMC. In contrast, inhibitors of nuclear factor kappa B (NF-κB) completely blocked CCL2 production in MLMC and BMMC but not in LAD 2 mast cells. Pertussis toxin and U0126, which, respectively, inhibit Gαi, extracellular signal-regulated kinase (ERK) phosphorylation substantially inhibited Pam 3Cys-induced CCL2 generation in LAD 2 mast cells but had little or no effect on chemokine generation in MLMC and BMMC. These findings suggest that TLR2 activation in human LAD 2 mast cells and MLMC/BMMC promotes the release of different classes of mediators via distinct signalling pathways that depend on Ca2+ mobilization and G protein usage.

Original languageEnglish (US)
Pages (from-to)412-420
Number of pages9
JournalImmunology
Volume119
Issue number3
DOIs
StatePublished - Nov 2006
Externally publishedYes

Fingerprint

Toll-Like Receptors
GTP-Binding Proteins
Mast Cells
Chemokines
Cytokines
NFATC Transcription Factors
NF-kappa B
Chemokine CCL2
Calcineurin
Extracellular Signal-Regulated MAP Kinases
Pertussis Toxin
Cyclosporine
Bone Marrow
Phosphorylation
Cell Line
Lung

Keywords

  • Chemokine
  • Cytokine
  • Mast cells
  • Signal transduction
  • TLR

ASJC Scopus subject areas

  • Immunology

Cite this

Distinct roles of Ca2+ mobilization and G protein usage on regulation of Toll-like receptor function in human and murine mast cells. / Zaidi, Asifa K.; Thangam, Elden Retna Raj B; Ali, Hydar.

In: Immunology, Vol. 119, No. 3, 11.2006, p. 412-420.

Research output: Contribution to journalArticle

Zaidi, Asifa K. ; Thangam, Elden Retna Raj B ; Ali, Hydar. / Distinct roles of Ca2+ mobilization and G protein usage on regulation of Toll-like receptor function in human and murine mast cells. In: Immunology. 2006 ; Vol. 119, No. 3. pp. 412-420.
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