Cytokine regulation of the expression of receptors for neurotransmitters

Abstract

The synaptic properties of a neuron depend not only on its transmitter phenotype, but also on its complement of receptors for neurotransmitters. Epigenetic signals that influence the expression of receptors may regulate synaptogenesis and/or the way a neuron reacts to injury. Previous studies have shown that the cytokines leukemia inhibitory factor (LIF) and ciliary neurotrophic factor (CNTF) stimulate normally noradrenergic sympathetic neurons to switch to a predominantly cholinergic and peptidergic phenotype. To determine whether such epigenetic signals also regulate receptor expression, we examined the effects of these cytokines on muscarinic and substance P receptors in sympathetic neurons. In dissociated cultures of the rat superior cervical ganglion (SCG), binding of the radiolabeled muscarinic ligand ({dollar}\sp3{dollar}H) -N-Methyl scopolamine was down-regulated after treatment with LIF or CNTF. Nuclease protection assays demonstrated that the predominant muscarinic receptor subtype in sympathetic neurons, m2, was also down-regulated after the same treatments. In contrast to the decrease in muscarinic receptors, levels of the mRNA encoding the substance P receptor (SPR) were increased by LIF or CNTF demonstrating that the cytokines differentially regulate muscarinic and SP receptors in these neurons. The cytokine interleukin-1{dollar}\beta{dollar} (IL-1{dollar}\beta{dollar}) similarly increased SPR mRNA in neonatal explant culture, but not in pure sympathetic neurons, suggesting that the cytokine acted on the non-neuronal cells. Conditioned medium from IL-1{dollar}\beta{dollar} stimulated fibroblasts or Schwann cells increased SPR mRNA levels in pure sympathetic neurons, and the effect could be blocked by a LIF antibody. This suggests that IL-1{dollar}\beta{dollar} stimulates release of LIF by non-neuronal cells. In vivo, SPR mRNA levels were also elevated after axotomy of the adult SCG, and this increase was preceded by an increase in LIF mRNA. In summary, several cytokines regulate not only transmitter but also receptor expression in sympathetic neurons. Such mechanisms may help to regulate receptor phenotype in the developing animal and in neuronal responses to injury in the adult.