IL-3 synergises with basophil-derived IL-4 and IL-13 to promote the alternative activation of human monocytes

Basophil-derived IL-4 is involved in the alternative activation of mouse monocytes, as recently shown in vivo. Whether this applies to human basophils and monocytes has not been established yet. Here, we sought to characterise the interaction between basophils and monocytes and identify the molecular determinants. A basophil-monocyte co-culture model revealed that IL-3 and basophil-derived IL-4 and IL-13 induced monocyte production of CCL17, a marker of alternative activation. Critically, IL-3 and IL-4 acted directly on monocytes to induce CCL17 production through histone H3 acetylation, but did not increase the recruitment of STAT5 or STAT6. Although freshly isolated monocytes did not express the IL-3 receptor α chain (CD123), and did not respond to IL-3 (as assessed by STAT5 phosphorylation), the overnight incubation with IL-4 (especially if associated with IL-3) upregulated CD123 expression. IL-3-activated JAK2-STAT5 pathway inhibitors reduced the CCL17 production in response to IL-3 and IL-4, but not to IL-4 alone. Interestingly, monocytes isolated from allergen-sensitised asthmatic patients exhibited a higher expression of CD123. Taken together, our data show that the JAK2-STAT5 pathway modulates both basophil and monocyte effector responses. The coordinated activation of STAT5 and STAT6 may have a major impact on monocyte alternative activation in vitro and in vivo.