Interleukin‐6‐mediated signaling in adrenal medullary chromaffin cells

Abstract

The pro-inflammatory cytokines, tumor necrosis factor-α and interleukin-1β/α modulate catecholamine secretion, and long-term gene regulation, in chromaffin cells of the adrenal medulla. Since interleukin-6 (IL6) also plays a key integrative role during inflammation, we have examined its ability to affect both tyrosine hydroxylase activity and adrenomedullary gene transcription in cultured bovine chromaffin cells. IL6 caused acute tyrosine/threonine phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), and serine/tyrosine phosphorylation of signal transducer and activator of transcription 3 (STAT3). Consistent with ERK1/2 activation, IL6 rapidly increased tyrosine hydroxylase phosphorylation (serine-31) and activity, as well as up-regulated genes, encoding secreted proteins including galanin, vasoactive intestinal peptide, gastrin releasing peptide and parathyroid hormone-like hormone. The effects of IL6 on the entire bovine chromaffin cell transcriptome were compared to those generated by G-protein coupled receptor (GPCR) agonists (histamine and pituitary adenylate cyclase-activating polypeptide) and the cytokine receptor agonists (interferon-α and tumor necrosis factor-α). Of 90 genes up-regulated by IL6, only 16 are known targets of IL6 in the immune system. Those remaining likely represent a combination of novel IL6/STAT3 targets, ERK1/2 targets and, potentially, IL6-dependent genes activated by IL6-induced transcription factors, such as hypoxia-inducible factor 1α. Notably, genes induced by IL6 include both neuroendocrine-specific genes activated by GPCR agonists, and transcripts also activated by the cytokines. These results suggest an integrative role for IL6 in the fine-tuning of the chromaffin cell response to a wide range of physiological and paraphysiological stressors, particularly when immune and endocrine stimuli converge.

Tyrosine hydroxylase phosphorylation in vivo

“…Interleukin 6 increased ERK activation, Ser31 phosphorylation and TH activity without changes at Ser40 or Ser19 (Jenkins et al . ). This shows that activation of ERK increases TH phosphorylation at Ser31 and TH activation in situ .…”

Extracellular gp96 is a crucial mediator for driving immune hyperactivation and liver damage

“…Hyperactivation of immune cells, including Kupffer cells, T cells, and natural killer (NK) cells, as well as the infiltration of large amounts of neutrophils in the liver, can aggravate the apoptosis or necrosis of hepatocytes. Inflammatory cytokines secreted by these immune cells, including TNF-α, IL-6, IFN-γ, and IL-1β, also contribute to the immune-mediated injury, in which TNF-α is considered to play a major role in cytokine-induced liver damage 5 – 7 . TNF-α both induces the apoptosis and necrosis of hepatocytes and stimulates the production of other inflammatory cytokines 8 .…”

Peripheral Lipopolysaccharide Challenge Induces Long-Term Changes in Tyrosine Hydroxylase Regulation in the Adrenal Medulla

“…While the capacity of IL‐4 to influence chromaffin cell regulation is unclear, IL‐6 has been shown to have a direct effect on chromaffin cells as IL‐6 receptors are expressed in chromaffin cells [Gadient et al, ]. IL‐6 has also been shown to activate the ERK pathway in chromaffin cells [Bunn et al, ; Jenkins et al, ]. This suggests a mechanism by which the increased IL‐6 levels acting on the IL‐6 receptor will activate the ERK pathway and then increase the transcription of TH via activation of CREB.…”

“…Classically, TH activity is modulated short‐term by increased phosphorylation of the serine 19, 31, and 40 residues (Ser19, Ser31, and Ser40) and long‐term by increased synthesis of TH protein [Dickson and Briggs, ]. Interestingly, TH activity can be modulated by cytokines, and these cytokines exert a variety of effects on activation of TH, either by short‐term non‐genomic actions via influx of the extracellular calcium into the cells and activation of protein kinases that increase TH phosphorylation or long‐term genomic actions via changing mRNA expression and protein synthesis [Douglas et al, ; Bunn et al, ; Tekin et al, ; Jenkins et al, ].…”