Interleukin-2-induced hepatic injury involves temporal patterns of cell adhesion in the microcirculation

The treatment of metastatic cancer with interleukin-2 (IL-2) is limited by systemic toxicities, including hepatic dysfunction. The objective of this study was to determine the cellular mechanisms of IL-2-induced hepatic injury. Intravital microscopy was used for the direct observation of the murine hepatic microcirculation after 2 h, 2 days, and 4 days of IL-2 treatment. At each interval, leukocyte- and platelet-endothelial adherence were observed and quantitated. Simultaneously, sinusoidal perfusion, serum levels of glutamate pyruvate transaminase, and edema were measured as indexes of hepatic toxicity. IL-2 increased neutrophil adhesion acutely in association with decreased sinusoidal perfusion. Leukocyte adhesion subsided at 2 days, but platelet-endothelial interactions were enhanced and 40% of mice receiving IL-2 had microvascular thrombi. These effects occurred in conjunction with decreased sinusoidal perfusion and the development of hepatic edema. After 4 days of IL-2, maximal hepatic edema, hypoperfusion, and increased serum levels of glutamate pyruvate transaminase were associated with increased lymphocyte adhesion and microvascular thrombosis. These data suggest coordinated, temporal roles of leukocytes and platelets in the generation of IL-2-induced hepatic injury.