Interleukin-6 Mediated Signalling in Adrenal Medullary Chromaffin Cells

Abstract

The secretion of catecholamines and neuropeptides by the adrenal medulla plays a central role in the physiological adaptation to stress. Its activity is regulated by multiple factors including neuronal, hormonal and paracrine signals. Recent evidence suggests that the adrenal medulla may also be responsive to immune-derived signals such as cytokines. Such an interaction may form part of a wider bi-directional relationship believed to exist between the immune and neuroendocrine systems, disturbance of which may contribute to a number of stress-related pathologies. This study has employed isolated bovine adrenal medullary chromaffin cells together with immunocytochemistry and Western blotting procedures to demonstrate the pro-inflammatory cytokine interleukin-6 (IL-6) has a direct action on these neuroendocrine cells. Incubation with IL-6 caused a transient increase in the phosphorylation and thus activation of pERK1/2. This activation may have implications for the regulation of tyrosine hydroxylase activity and thus catecholamine synthesis. In addition to ERK activation IL-6 stimulated the tyrosine phosphorylation and nuclear localisation of signal transducer and activator of transcription-3 (STAT3) in approximately 70% of the cells, suggesting the cytokine may regulate chromaffin cell gene transcription. IL-6 also increased the serine phosphorylation of STAT3, probably through an ERK1/2 and Ca2+-influx dependent pathway. The biological significance of serine phosphorylation of STAT3 is unresolved. These data provide evidence that the neuroendocrine chromaffin cells are sensitive to IL-6, suggesting a pathway linking immune-derived signals to the adrenal medullary stress response. Importantly this IL-6 response has the potential to regulate both acute enzyme activity and gene expression, with potentially important implications for the homeostatic regulation of the inflammatory response.