Abstract
The immune-regulatory compound histamine is involved in the metabolism of the essential skin component hyaluronan (HA). We previously reported that histamine up-regulates the expression of HYBID (hyaluronan-binding protein involved in hyaluronan depolymerization, also called CEMIP or KIAA1199), which plays a key role in HA degradation. However, no information is available about histamine's effects on HA synthase (HAS) expression, the molecular sizes of HA species produced, and histamine receptors and their signaling pathways in skin fibroblasts. Moreover, histamine's effects on photoaged skin remain elusive. Here, we show that histamine increases HA degradation by up-regulating HYBID and down-regulating HAS2 in human skin fibroblasts in a dose- and time-dependent manner and thereby decreases the total amounts and sizes of newly produced HA. Histamine H1 blocker abrogated the histamine effects on HYBID up-regulation, HAS2 suppression, and HA degradation. Histamine H1 agonist exhibited effects on HA levels, composition, and breakdown similar to those of histamine. Of note, blockade of protein kinase Cδ or PI3K-Akt signaling abolished histamine-mediated HYBID stimulation and HAS2 suppression, respectively. Immunohistochemical experiments revealed a significant ∼2-fold increase in tryptase-positive mast cells in photoaged skin, where HYBID and HAS2 expression levels were increased and decreased, respectively, compared with photoprotected skin. These results indicate that histamine controls HA metabolism by up-regulating HYBID and down-regulating HAS2 via distinct signaling pathways downstream of histamine receptor H1. They further suggest that histamine may contribute to photoaged skin damage by skewing HA metabolism toward degradation.
Highlights
The immune-regulatory compound histamine is involved in the metabolism of the essential skin component hyaluronan (HA)
Our data in the present study provide, to the best of our knowledge, the first evidence that histamine contributes to the production of lower-molecular-weight HA through up-regulation of HYBID and down-regulation of HAS2 in skin fibroblasts and suggest that mast cell– derived histamine may play a role in aberrant HA metabolism in photoaged skin
To the best of our knowledge, we have demonstrated for the first time that histamine decreases total amount and molecular size of newly produced HA by the increased HYBID-mediated HA degradation and the suppressed HAS2-mediated HA synthesis in human skin fibroblasts
Summary
We first examined the dose- and time-dependent effects of histamine on the HYBID expression in normal human embryonic skin fibroblasts (Detroit 551 cells). Normal human adult skin fibroblasts (NHDF-Ad cells) showed the up-regulation of mRNA and protein expression of HYBID, up to an ϳ2-fold increase compared with the original level, after treatment with histamine (Fig. S2, A and B), whereas neither down-regulation of the HAS2 and HAS3 expression nor HA production was seen by histamine treatment (Fig. S2, D–F). These data suggest that histamine commonly up-regulates HYBID expression, but histamine-mediated HAS down-regulation may be cell type–specific. The values represent means Ϯ S.D. (n ϭ 3)
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