Staphylococcal Extracellular Complement-Binding Protein Induces IL-4 Production in Murine Basophils.

Abstract

Staphylococcus aureus is responsible for a wide range of pyogenic infections, food poisoning, and allergic inflammation. S. aureus produces a very wide variety of proteinaceous exotoxins, which are classified by structure as β-barrel pore-forming toxin, oligonucleotide/oligosaccharide-binding (OB)-fold/β-grasp proteins, and triple-helix bundle-containing proteins. We previously reported that three staphylococcal exotoxins belonging to the first two groups activate basophils and mast cells, which are innate immune cells that play a central role in allergic inflammation. In this study, we focused on a group of triple-helix bundle-containing toxins and examined their ability to activate murine bone marrow-derived mast cells and basophils. Extracellular complement-binding protein (Ecb), previously known as a complement inhibitor, was found to induce IL-4 and IL-6 production in basophils but not that of IL-6 and IL-13 in mast cells. Ecb did not induce IL-4 production in murine splenocytes or CD4+ T cells, suggesting that it is a basophil-specific activator. Ecb-induced IL-4 expression in basophils in the absence of serum. The C3-binding-deficient mutant of Ecb also activated basophils, indicating that Ecb activates basophils independently of its complement-inhibiting activity. Dasatinib, a Src kinase inhibitor, prevented Ecb-induced IL-4 production in basophils, suggesting that the activation required a Src family kinase. These findings reveal a novel function of Ecb, that is, the activation of basophils to produce IL-4 in an IgE-independent manner, and suggest a dual Ecb contribution to immune evasion-by interfering with complement activation and skewing Th2 immunity-and a role in the development of allergic inflammation-by inducing IL-4 production.