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Mast cells (MCs), unique cellular elements of the body, are commonly associated with IgE-mediated reactions and manifestations of Th2-type immunity. A key characteristic of the lineage is its heterogeneity, with subsets displaying significant variation depending on maturation stage, species, tissue, microenvironment and other. Heterogeneity also affects MC responses to extracellular cues. Indeed, IL-4, the signature cytokine of Th2-immunity, can affect MCs in opposing ways ranging from the induction of apoptosis to positive regulation of lineage characteristics. It is unknown, however, whether IL-4 alters the phenotype of terminally differentiated human cutaneous MCs. Using our well-established technique for homogeneous purification of human skin MCs, we now report that prolonged contact with IL-4 not only increases MC expansion, but also phenotypically and functionally re-shapes the cells. FcεRI cell surface expression, FcεRIα-specific mRNA and FcεRI-mediated histamine release are all augmented by IL-4, while histamine release elicited by the non-immunological stimulus, substance P, remains unaffected. IL-4's potential to mold MCs is broad and similarly detectable across donors. Intriguingly, IL-4 impacts granule-associated mediators, especially histamine whose synthesis is boosted in the presence of IL-4. To our knowledge, an increase in histamine production by IL-4 has not been described yet for any type of MCs, but may well contribute to its pro-allergic effect given the significance of this biogenic amine to allergic symptoms. Collectively, IL-4 alters human skin MCs after long-term exposure mimicking chronic disorders by strengthening MC numbers and intensifying processes associated with allergic inflammation. [ABSTRACT FROM AUTHOR]