Spinal Interleukin-1 Beta Induces Mechanical Spinal Hyperexcitability In Rats: Interactions And Redundancies With Tnf And Il-6

Both spinal tumor necrosis factor (TNF) and interleukin-6 (IL-6) contribute to the development of "mechanical" spinal hyperexcitability in inflammatory pain states. Recently, we found that spinal sensitization by TNF was significantly reduced by blockade of spinal IL-6 signaling suggesting that IL-6 signaling is involved in spinal TNF effects. Here, we explored whether spinal interleukin-1 beta (IL-1 beta), also implicated in inflammatory pain, induces "mechanical" spinal hyperexcitability, and whether spinal IL-1 beta effects are related to TNF and IL-6 effects. We recorded the responses of spinal cord neurons to mechanical stimulation of the knee joint in vivo and used cellular approaches on microglial and astroglial cell lines to identify interactions of IL-1 beta, TNF, and IL-6. Spinal application of IL-1 beta in anesthetized rats modestly enhanced responses of spinal cord neurons to innocuous and noxious mechanical joint stimulation. This effect was blocked by minocycline indicating microglia involvement, and significantly attenuated by interfering with IL-6 signaling. In the BV2 microglial cell line, IL-1 beta, like TNF, enhanced the release of soluble IL-6 receptor, necessary for spinal IL-6 actions. Different to TNF, IL-1 beta caused SNB-19 astrocytes to release interleukin-11. The generation of "mechanical" spinal hyperexcitability by IL-1 beta was more pronounced upon spinal TNF neutralization with etanercept, suggesting that concomitant TNF limits IL-1 beta effects. In BV2 cells, TNF stimulated the release of IL-1Ra, an endogenous IL-1 beta antagonist. Thus, spinal IL-1 beta has the potential to induce spinal hyperexcitability sharing with TNF dependency on IL-6 signaling, but TNF also limited IL-1 beta effects explaining the modest effect of IL-1 beta.