Interleukin-6 Signalling in the Murine Adrenal Gland

The adrenal gland is instrumental in the maintenance and restoration of homeostasis. This is mediated in part by catecholamine and glucocorticoid secretion from the adrenal medulla and cortex respectively. The catecholamine secreting chromaffin cells respond to a wide range of stressors which are conveyed to the gland via neuronal, hormonal and paracrine pathways. Included among these are signals of immune origin. It has been shown that isolated chromaffin cells, maintained in culture, are responsive to a number of cytokines, including interleukin-6 (IL-6). This observation underlines a functional link between the immune and stress systems. The central aim of this investigation was to determine if IL-6 also targets the adrenal medulla in the live animal. Immunohistochemical and PCR analysis revealed the presence of IL-6 receptors in the adrenal chromaffin cells of the adult male mouse. Acute exposure to exogenous IL-6 did not however indicate an IL-6 responsiveness in these cells (as demonstrated by the downstream signalling molecule, pSTAT3). In contrast, responsive cells were seen in the adrenal vasculature and cortex. Given the lack of convincing evidence for IL-6 receptor expression in these tissues it is proposed that these responses occurred via a trans-signalling mechanism involving the soluble IL-6 receptor. More prolonged elevation of IL-6 following endotoxin (LPS) administration significantly increased pSTAT3 signalling in the chromaffin cells. The involvement of IL-6 in this response was demonstrated by its suppression by antibodies against IL-6. This LPS-initiated response was accompanied by increased mRNA expression for the pSTAT3 regulator SOCS3 and the adrenal medullary peptides VIP and galanin, an observation consistent with previous findings in isolated chromaffin cells. LPS did not however increase the expression or phosphorylation status of tyrosine hydroxylase (TH) suggesting a lack of a direct effect on the catecholamine synthesising capacity of the chromaffin cells. In order to investigate the specificity of this IL-6 action on the adrenal medulla relative to other stress inputs, a comparison was made with animals subjected to a chronic mild variable stress protocol (CVS). Interestingly while the adrenals of these animals lack evidence of IL-6 signalling (elevation of SOCS3 mRNA) they did show increased VIP and galanin expression. In contrast to LPS treatment CVS also increased the potential catecholamine synthesising capacity of the cells by raising TH mRNA, TH protein and its phosphorylation status. In addition, the male and female response to CVS also indicated sex differences, with females being more responsive, both in terms of neuropeptide gene expression and catecholamine synthesising enzyme activity. These observations indicate that adrenal chromaffin cells in vivo are sensitive to IL-6 and are likely to alter their neuropeptide output in response to this signal. It is hypothesised that increased secretion of the neuropeptides may then act within the gland to potentially modulate both its catecholamine and steroid output when subject to immune-derived stress