We have previously reported a seasonal increase in angioedema, but not urticaria, in the summer months, peaking in June. Melatonin, a factor responsible for sleep-wake cycles, is decreased during long summer days. As melatonin is known to suppress eNOS, which is upregulated by bradykinin, we hypothesized that decreased melatonin levels are associated with increased nitric oxide production from stimulated PBMC.
Blood was drawn from healthy subjects (n=6) between 8 - 11 AM and PBMC (3x106/ml) were stimulated with bradykinin (100 nmol/ml), ± hIL-15 (1 µg/ml), ±IL-18 (1 ug/ml)(Group1), recombinant human melatonin (1,10, 100 pmol/ml, M1, M2, M3, respectively), and IFN-gamma (10 ng/ml)/ Vitamin D3 (20 pmol/ml)(Group 2). Cells were incubated for 5 days, and nitric oxide levels determined using Griess reaction.
Stimulation with Group 1 did not increase NO production above baseline (base: 0.61±0.76 μM, Group 1: 0.63±0.79 μM, p=0.62). Addition of M1-M3 to Group 1 did not alter NO production (0.59±0.72 μM, 0.62±0.66 μM, 0.59±0.76 μM) (p=ns). However, addition of Group 2 to Group1/M1-M3 treated PBMCs resulted in a significant increase in NO: (1.84±0.21 μM 1.48±0.42 μM, 1.02±0.52 μM) (p<0.01, p=0.046, p=0.26, respectively).
Prolonged, low daytime levels of melatonin increase nitric oxide production from Interferon-gamma stimulated leukocytes and may contribute to seasonal angioedema.