Heparan Sulfate-Bound Dimeric IL-2: A Potential Mediator of Renal Ischemic Injury

Interleukin-2 (IL-2) is a cytokine critical to normal immune function. Our laboratory has shown that IL-2 is retained in tissues by heparan sulfate (HS). While known as a monomer, a dimeric form of IL-2 was previously identified in fish optic neurons, and this form was toxic to oligodendrocytes. Given this observation, we asked whether dimeric IL-2 is found in mammalian tissues. Murine and human aorta and kidney were assessed by Western blot for the presence of IL-2. Dimeric (30 kD) IL-2 was identified in each tissue. Heparinase digestion of tissues liberated dimeric IL-2, suggesting that the dimer is bound, at least in part, by HS. To ascertain whether dimeric IL-2 is cytotoxic, we treated cultures of renal epithelial cells with increasing concentrations of dimeric IL-2, isolated by electroelution. Signs of cytotoxicity were evident within 15 minutes of dimer addition. Commercial IL-2, isolated identically to dimeric IL-2, was not cytotoxic. Systemic administration to mice of 10 μg of dimeric IL-2 induced vacuolization of renal epithelium, a morphology typically seen with ischemic injury. Finally, murine kidneys subjected to 60 minutes of ischemia, compared to sham controls, expressed greatly increased amounts of dimeric IL-2 in tissue homogenates. These results suggest that dimeric IL-2 may contribute to acute tubular necrosis and, in turn, renal dysfunction. This work was supported by institutional funds.