gp130 cytokines stimulate tyrosine hydroxylase proteasomal degradation and activity in sympathetic neurons

Tyrosine hydroxylase (TH), the rate-limiting enzyme in norepinephrine synthesis, is locally depleted in cardiac sympathetic nerves after myocardial infarction due to cytokine signaling, but the mechanism was unclear. This study shows that gp130 cytokines promote TH proteasomal degradation via ubiquitination, requiring ERK1/2 activation, and reduce TH half-life in sympathetic neurons. Surprisingly, cytokines also increased TH enzymatic activity, enhancing L-DOPA production. These findings reveal that inflammatory cytokines regulate both TH protein stability and activity, offering insight into neurotransmission changes during inflammation and contributing to understanding catecholaminergic dysfunction in neurological disease.