Basophils induce protumorigenic cytokines from A549 lung adenocarcinoma via mechanisms requiring IgE, galectin-3, and IL-3 priming.

Galectin-3 (Gal-3) is implicated in innate immune cell activation in a host of diseases/conditions. We identified a unique response whereby human basophils secrete interleukin (IL)-4/IL-13 when cocultured with A549 cells-lung adenocarcinoma. While displaying parameters consistent with standard IgE-dependent activation, these Gal-3-dependent responses occurred in the absence of specific IgE/allergens and required cell-to-cell contact. We now hypothesize that this mode of activation also impacts A549 function. Our findings show that cytokines are induced in basophil/A549 cocultures that are not detected when either cell is cultured alone, in particular IL-6. As previously shown for IL-4/IL-13, IL-6 production also required cell-to-cell contact and was dependent on A549-Gal-3, as clones deficient of this lectin induced less cytokine. Using culture-derived basophils (CDBAs), we demonstrate that the IL-6 response and production of another tumorigenic factor, vascular endothelial growth factor A (VEGF-A), are induced in CDBA/A549 cocultures but only after passively sensitizing CDBAs with IgE, in a manner similar to IL-4/IL-13. However, IgE-dependent activation of basophils/CDBAs cultured alone failed to induce IL-6/VEGF. Importantly, IL-3-primed basophils, even those fixed with paraformaldehyde, readily induced IL-6/VEGF-A in cocultures, thus verifying that these cytokines are derived from A549. Overall, these results suggest a complex mechanism whereby Gal-3/IgE interactions between IL-3-primed basophils and A549 have the potential to modulate cytokine production by both cells. With Gal-3 implicated not only in many diseases ranging from asthma to cancer, but also in normal physiological conditions, such as wound healing, these findings are predicted to provide insight into the molecular mechanisms by which this lectin (and IgE) functions in these processes.