Nobiletin enhances plasma Interleukin‐6 and C‐X‐C motif chemokine ligand 1 levels that are increased by treadmill running

Exercise increases the muscular secretion of Interleukin‐6 (IL‐6), which is partially regulated by β2‐adrenergic receptor signaling. Nobiletin is a polymethoxyflavone (PMF) found in citrus fruits that induces the secretion of IL‐6 from C2C12 myotubes, but it remains unclear whether nobiletin promotes IL‐6 secretion during exercise. The aim of this study was to clarify the effects of nobiletin on IL‐6 secretion during exercise. Nobiletin and epinephrine were found to synergistically increase IL‐6 secretion from differentiated C2C12 cells, which was suppressed by the inhibition of adenylyl cyclase (AC) or protein kinase A (PKA). Treadmill running for 60 min increased plasma levels of IL‐6, epinephrine, and norepinephrine in rats. Nobiletin (5 mg/kg) orally administered 30 min before running increased plasma IL‐6 levels further, although it did not increase plasma epinephrine and norepinephrine. In a similar manner to IL‐6, nobiletin and epinephrine synergistically increased the secretion of C‐X‐C motif chemokine ligand 1 (CXCL‐1) from C2C12 cells, or the increase in plasma CXCL‐1 was enhanced by nobiletin after treadmill running of rats. Our results suggest that nobiletin promotes IL‐6 and CXCL‐1 secretion from skeletal muscle by synergistic enhancement of the PKA pathway in β2‐adrenergic receptor signaling.