IL-1β augments HS-induced increase in intracellular Ca through polysulfides generated from HS/NO interaction.

HS has excitatory and inhibitory effects on Ca signals via transient receptor potential ankyrin 1 (TRPA1) and ATP-sensitive K channels, respectively. HS converts intracellularly to polysulfides, which are more potent agonists for TRPA1 than HS. Under inflammatory conditions, changes in the expression and activity of these HS target channels and/or the conversion of HS to polysulfides may modulate HS effects. Effects of proinflammatory cytokines on HS-induced Ca signals and polysulfide production in RIN14B cells were examined using fluorescence imaging with fura-2 and SSP4, respectively. NaS, a HS donor, induced 1) the inhibition of spontaneous Ca signals, 2) inhibition followed by [Ca] increase, and 3) rapid [Ca] increase without inhibition in 50% (23/46), 22% (10/46), and 17% (8/46) of cells tested, respectively. IL-1β augmented HS-induced [Ca] increases, which were inhibited by TRPA1 and voltage-dependent L-type Ca channel blockers. However, IL-1β treatment did not affect [Ca] increases evoked by a TRPA1 agonist or high concentration of KCl. NaS increased intracellular polysulfide levels, which were enhanced by IL-1β treatment. A NOS inhibitor suppressed the increased polysulfide production and [Ca] increase in IL-1β-treated cells. These results suggest that IL-1β augments HS-induced [Ca] increases via the conversion of HS to polysulfides through NO synthesis, but not via changes in the activity and expression of target channels. Polysulfides may play an important role in the effects of HS during inflammation.