Cis-UCA appears to be a promising anti-inflammatory compound because we observed here that cis-UCA reduced the secretion of IL-1β and IL-18 as well as the activity of caspase-1 in HCE cells. Additionally, we demonstrated that cis-UCA possessed therapeutic properties because it decreased the secretion of IL-6 and IL-8 and alleviated cell death even when administered after the UV-B exposure. We have recently confirmed in a clinical phase I study that 0.5% and 2.5% cis-UCA eye drops are well-tolerated after topical administration to the cornea
50 and there was no evidence of systemic accumulation or systemic or local side effects upon repeated topical administration of 5% cis-UCA in randomized phase I/IIa dermatological trials.
51 Although the mechanism behind the capacity of cis-UCA to regulate immune responses has been studied widely past 3 decades, it still remains fully unsolved. In our previous studies, cis-UCA was able to prevent IL-8 and IL-6 secretion via the c-Jun/activator protein-1 and JNK/mitogen activated protein kinase pathways.
29,30 Instead, Walterscheid et al. have previously reported that the immune suppressive effect of cis-UCA is mediated through the activation of 5-hydroxytryptamine receptor 2 A (5-HTR2A) in mice,
52 whereas Cloëz-Tayarani and colleagues showed that the stimulation of 5-HT rather increased than decreased the production of IL-1β through 5-HTR2A in LPS-stimulated human PBMCs.
53 In another study, 5-HT stimulation increased the production of IL-1β but not that of IL-18 in LPS-treated human blood monocytes.
54 In the study of Dürk et al., IL-1β secretion was mediated via 5-HTR3, 5-HTR4, and 5-HTR7 instead of 5-HTR2A.
54 In our present study, productions of IL-1β and IL-18 were regulated via distinct signaling pathways but cis-UCA reduced the secretion of both of these cytokines, which along with previous findings propose that IL-1β and IL-18 secretion may not be regulated by 5-HTR2A. Alternatively, cis-UCA has been reported to exert a protodynamic effect in cell cultures, which means that it is capable of transporting protons from a mildly acidic extracellular matrix into the cell.
55 Because extracellular acidosis is a danger signal for the activation of NLRP3 inflammasome through the K
+ efflux,
56 it could be hypothesized that cis-UCA acts to regulate the balance of K
+ levels between the cytosol and the extracellular space. UV-B is known to trigger K
+ efflux in human corneal limbal epithelial cells,
57 and the inhibition of K
+ efflux is one way to inhibit inflammasome activation and reduce the levels of IL-1β.
58,59 Moreover, reactive oxygen species production has been shown to increase the amounts of the pro-form of IL-1β and to promote its maturation via the NLRP3 inflammasome in hyperosmolarity-induced HCE-2 cells.
60 That could serve as another way to investigate the silencing mechanism of cis-UCA in UV-B-activated inflammasome signaling. The present study provides new insights to study molecular mechanism of cis-UCA, which has now been associated for the first time with the UV-B-induced activation of inflammasomes in human corneal epithelial cells.