Abstract
Osteopontin (OPN) is an Arg-Gly-Asp (RGD)-containing extracellular matrix protein which is upregulated in inflamed tissues and has been reported to modulate mast cell activities in mice. Due to the known heterogeneity among mast cells of different species and the important roles of mast cells in allergic reactions, we investigated the effects of human OPN (hOPN) on human mast cell activities. Mature primary human cultured mast cells (HCMC) were derived from peripheral blood CD34+ progenitors and the modulation of their activation by soluble and plate-bound immobilized hOPN were examined by studying their release of inflammatory mediators (histamine, IL-5, IL-8, TNF-α, and VEGF) and matrix adhesion following stimulation by anti-IgE. Immobilized hOPN enhanced the adhesion, but suppressed the release of IL-5, IL-8, and TNF-α of anti-IgE-activated HCMC while soluble hOPN failed to demonstrate any significant effects. By employing cyclic RGD peptide and neutralizing antibodies against different classes of integrin and CD44, we demonstrated that the interaction of immobilized hOPN and HCMC was mediated by the RGD domain of hOPN and integrin but not CD44 on HCMC. Our results suggest that immobilized hOPN anchored to extracellular matrix can regulate adaptive immunity in humans by retaining mast cells at the site of inflammation and suppressing anti-IgE-induced cytokine release from HCMC.
Highlights
Mast cells are immune effectors abundantly located in tissues that interface with external environment such as the respiratory tract where they are found around peripheral nerves, blood vessels, and lymph vessels
IgE-sensitized human cultured mast cells (HCMC) spontaneously released around 5% of total cellular histamine and 100 ng/106 cells of VEGF but no detectable levels of IL-8, TNF-α, and IL-5 in culture medium alone
While incubation with either form of human OPN (hOPN) did not significantly affect the basal spontaneous release of these mediators, anti-IgE activation significantly increased the release of histamine and VEGF and induced the release of IL-5, IL-8, and TNF-α
Summary
Mast cells are immune effectors abundantly located in tissues that interface with external environment such as the respiratory tract where they are found around peripheral nerves, blood vessels, and lymph vessels. They are essential in the pathogenesis of allergic reactions through the dimerization of cell surface high affinity IgE receptors (FcεRI) mediated by crosslinking of receptor bound IgE molecules by allergens [1, 2]. The extracellular matrix protein, osteopontin (OPN) has recently been proposed to modulate mast cell functions [3]
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