RNA from rat dorsal root ganglia was analyzed in search of potentially beneficial cytokines that are induced in dorsal root ganglia by nerve injury. By reverse transcription, the PCR, and Southern blotting, interleukin-6 mRNA was detected during development but not in normal adult dorsal root ganglia, reappeared within 1 d of sciatic nerve transection, was maximally increased after 2 and 4 d, and decreased below the threshold of detection within 1 week. By RNase protection assay, interleukin-6 mRNA was consistently present in RNA from dorsal root ganglia removed from rats 4 d following transection but not in control dorsal root ganglia. Interleukin-6 bioactivity was also present in dorsal root ganglia following nerve injury. By in situ hybridization, interleukin-6 mRNA was localized within large and medium- sized axotomized neurons. In summary, some sensory neurons respond to axotomy with a brisk transient increase in synthesis of interleukin-6. Injury to the sciatic nerve also induced mRNAs for interleukin-1 beta and tumor necrosis factor-alpha in dorsal root ganglia. The inductions of interleukin-1 beta and tumor necrosis factor-alpha mRNAs were later and more sustained than that of interleukin-6 mRNA. The cellular sources of these two cytokines have not been defined.

In low-density, serum-free cultures of neurons from embryonic rat dorsal root ganglia, interleukin-6 supports the survival of less than one third of the neurons yet virtually all of them bear interleukin-6 alpha-receptors. A finding that might explain this selectivity is that interleukin-6 acts on sensory neurons in culture through a mechanism requiring endogenous brain-derived neurotrophic factor. Antibodies or a trkB fusion protein that block the biological activity of brain-derived neurotrophic factor synthesized by dorsal root ganglion neurons also block the survival-promoting actions of interleukin-6 on these neurons. Two results indicate that interleukin-6 influences synthesis of brain-derived neurotrophic factor in adult dorsal root ganglion neurons. Intrathecal infusion of interleukin-6 in rats increases the concentration of brain-derived neurotrophic factor mRNA in rat lumbar dorsal root ganglia. The induction of brain-derived neurotrophic factor in dorsal root ganglion neurons that is seen after nerve injury in rats or wild-type mice is severely attenuated in mice with null mutation of the interleukin-6 gene. In brief, the ability of interleukin-6 to support the survival of embryonic sensory neurons in vitro depends upon the presence of endogenous brain-derived neurotrophic factor and the induction of brain-derived neurotrophic factor in injured adult sensory neurons depends upon the presence of endogenous interleukin-6.

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