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

Abstract

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.