Interleukin-1 Mediates Induction of Tolerance to Global Ischemia in Gerbil Hippocampal CA1 Neurons

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Abstract
A series of experiments was performed to determine the role of interleukin (IL)-1 in the induction of tolerance to global ischemia in Mongolian gerbils. In Group I, a 2-min “preconditioning” ischemia protected CA1 hippocampal neurons in gerbils subjected to 3.5 min ischemia 3 days later. CA1 neuronal density was: sham, 171 ± 3/mm; 3.5 min ischemia, 30 ± 30/mm; 2 and 3.5 min ischemia 162 ± 6/mm. Experiments in Group II addressed the role of IL-1 in the induction of tolerance by sublethal ischemia. Arterial IL-1α and IL-Iβ became elevated between 1 and 3 days after a 2-min ischemic exposure. IL-1α was: sham, 6.4 ± 0.6 ng/ml; and 2-day, 10.2 ± 1.2 ng/ml. IL-1β was: sham, 6.4 ± 0.5 ng/ml; and 2-day, 17.3 ± 2 ng/ml. Recombinant human IL-1 receptor antagonist (IL-1ra) i.p. blocked ischemic tolerance induction by 2-min preconditioning ischemia: 2-min ischemia + vehicle, 162 ± 6/mm; and 2-min ischemia + IL-1ra, 67 ± 17/mm. Experiments in Group III assessed the capacity of IL-1 to induce tolerance to brain ischemia. IL-1α i.p. (0, 10, 20 μg/kg) for 3 days prior to 3.5-min forebrain ischemia provided significant CA1 neuroprotection in a dose-dependent manner: 2 ± 2, 68 ± 83, and 129 ± 42/mm, respectively. IL-1β (15 μg/kg) in combination with either IL-1ra (100 mg/kg) or IL-1ra vehicle i.p. on the same schedule demonstrated a significant CA1 neuroprotection that could be nullified by IL-1ra: IL-1β + IL-1ra vehicle, 153 ± 16/mm; and IL-1β + IL-1ra, 67 ± 36/mm. Recognition that tolerance arises from stimulation of a known receptor (IL-1RI) permits molecular analysis of the intracellular signaling that is critical for production of that state.