Interleukin-2 induces increased platelet-endothelium interactions: a potential mechanism of toxicity.
Cancer immunotherapy with interleukin-2 (IL-2) is limited by side effects that may cause organ dysfunction. The role of platelets in the generation of IL-2-induced organ dysfunction has not been studied, although various studies have shown that IL-2 therapy activates both platelets and the vascular endothelium. We hypothesized that IL-2 therapy may enhance the thrombogenic response to inflammatory stimuli through increased platelet-endothelial interactions and that these effects could lead to the development of organ dysfunction. C57BI/6 mice were treated with IL-2 intraperitoneally for 2 hours (short term) or 2 to 5 days (long term) and prepared for in vivo microscopy of the ear microcirculation. Mice were injected intra-arterially with fluorescein isothiocyanate conjugated to bovine serum albumin (FITC-BSA). Blue light activation of the FITC-BSA in ear arterioles induced thrombus formation. The time to initial thrombus formation was measured as an index of thrombogenicity. Platelet function was analyzed by aggregometry and platelet expression of IL-2 receptors, and the adhesion molecule lymphocyte function-associated antigen-1 (LFA-1) was analyzed by flow cytometry. Organ dysfunction was evaluated by serum markers. The administration of both short-term and long-term IL-2 reduced the time to initial thrombus formation as compared with controls. In vitro platelet aggregometry revealed no acute alterations in platelet function; however, long-term IL-2 treatment resulted in decreased disaggregation rates. There were no platelet IL-2 receptors present, and the expression of the adhesion molecule LFA-1 was not altered by IL-2. Increased thrombogenicity occurred before the generation of organ dysfunction. These data suggest that increased platelet adherence induced by IL-2 is caused by effects on the endothelium that could result in microvascular thrombus formation and contribute to organ dysfunction.
Lentsch
A B
AB
Department of Physiology and Biophysics, University of Louisville, KY, USA.
Edwards
M J
MJ
Miller
F N
FN
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects* / Q000502:physiology*; D002417:Cattle; D003094:Collagen / Q000494:pharmacology; D004423:Ear / Q000098:blood supply; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology*; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives; D007376:Interleukin-2 / Q000494:pharmacology* / Q000506:poisoning*; D008027:Light; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D012710:Serum Albumin, Bovine; D013927:Thrombosis / Q000209:etiology
D007376:Interleukin-2; D016169:Lymphocyte Function-Associated Antigen-1; C039217:fluorescein isothiocyanate bovine serum albumin; D012710:Serum Albumin, Bovine; D000244:Adenosine Diphosphate; D003094:Collagen; D016650:Fluorescein-5-isothiocyanate