AbstractCOVID-19 is the global pandemic that affected our population in the past two years. Considerable research has been done to better understand the pathophysiology of this disease and to identify new therapeutic targets, especially for severe cases. Galectin-3 (Gal-3) is a receptor present at the surface of different cell types, namely epithelial and inflammatory cells, which has been described as a severity marker in COVID-19. The activation of Gal-3 through its binding protein (Gal-3BP) is directly linked to the production of pro-inflammatory cytokines that contribute for the cytokine storm (CS) observed in severe COVID-19 patients. Here, we show that D2, a recombinant fragment of the lectin-binding region of Gal-3BP was able to stimulate the expression of IL-6 in colon and lung epithelial cell lines in β-galactoside dependent manner. We further show that D2-induced IL-6 augmentation was reduced by the anti-Gal-3BP monoclonal antibody 1959. Our data confirm and extend prior findings of Gal-3BP mediated IL-6 induction, enlightening the potential of its antibody-mediated s blockage for the prevention and treatment of CS and severe disease in COVID-19 patients.