IL-1β directly excites isolated rat supraoptic neurons via upregulation of the osmosensory cation current

Previous studies have shown that IL-1 beta can excite the magnocellular neurosecretory cells (MNCs) of the hypothalamus. However, it is not known whether IL-1 beta can have direct IL-1 receptor type 1 (IL-1R1)-mediated effects on MNCs, and little is known about the cellular mechanisms by which IL-1 beta influences electrical activity in these cells. Here, we used patch-clamp recordings to examine the effects of IL-1 beta on acutely isolated rat MNCs. We found that IL-1 beta directly excites MNCs in a dose-dependent manner and that this response can be blocked by an inhibitor of the IL-1R1. Voltage-clamp analysis of the current evoked by IL-1 beta revealed a linear current-voltage relationship between -90 and -20 mV, and a reversal potential near -35 mV. This value was not affected by reducing the concentration of chloride ions in the external solution, indicating the involvement of a nonselective cation conductance. The effects of IL-1 beta were inhibited by Na-salicylate, an inhibitor of cyclooxygenase. Moreover. the effects of IL-1 beta were mimicked and occluded by PGE(2), and were inhibited by AH-23848, an antagonist of the PGE(2) type 4 (i.e., EP4) receptor. The current evoked by IL-1 beta was also abolished by 100 mu M gadolinium (Gd3+), but was significantly larger when examined in cells preshrunk by negative pressure applied via the recording pipette. IL-1 beta alone did not cause changes in cell volume nor in the mechanosensitivity of MNCs. We conclude that IL-1 beta directly excites MNCs via an IL-1R1-mediated induction of PGE(2) synthesis and EP4 receptor-dependent autocrine upregulation of the nonselective cation conductance that underlies osmoreception.