The present invention resides in the discovery that the specific interaction between Myeloid Differentiation factor 2 (MD2) and integrin, especially integrin αvβ3, is involved in cellular signaling mediated by MD2-integrin, such as inflammatory response including sepsis. Thus, this invention provides for a novel method for inhibiting integrin signaling by using an inhibitor of MD2-integrin binding, such as a dominant negative mutant of MD2 without integrin-binding capability. A method for identifying inhibitors of MD2-integrin binding is also described. Further disclosed are polypeptides, nucleic acids, host cells, and corresponding compositions for inhibiting MD2-integrin signaling.