Resolvin D2 and Resolvin D1 Differentially Activate Protein Kinases to Counter-Regulate Histamine-Induced [Ca2+]i Increase and Mucin Secretion in Conjunctival Goblet Cells.

Menglu Yang,Charles N Serhan,Darlene A Dartt,Nora Botten,Robin Hodges,Jeffrey Bair,Tor P Utheim

doi:10.3390/ijms23010141

Abstract

Resolvin (Rv) D2 and RvD1 are biosynthesized from docosahexaenoic acid (DHA) and promote resolution of inflammation in multiple organs and tissues, including the conjunctiva. Histamine is a mediator produced by mast cells in the conjunctiva during the allergic response. We determined the interaction of RvD2 with histamine and its receptor subtypes in cultured conjunctival goblet cells and compared them with RvD1 by measuring intracellular [Ca2+] and mucous secretion. Treatment with RvD2 significantly blocked the histamine-induced [Ca2+]i increase as well as secretion. RvD2 and RvD1 counter-regulate different histamine receptor subtypes. RvD2 inhibited the increase in [Ca2+]i induced by the activation of H1, H3, or H4 receptors, whereas RvD1 inhibited H1 and H3 receptors. RvD2 and RvD1 also activate distinct receptor-specific protein kinases to counter-regulate the histamine receptors, probably by phosphorylation. Thus, our data suggest that the counter-regulation of H receptor subtypes by RvD2 and RvD1 to inhibit mucin secretion are separately regulated.

Highlights

Allergic conjunctivitis is a predisposition to hypersensitivity reactions upon exposure to specific environmental antigens and is characterized by ocular symptoms, such as itching, blurry vision, redness, and watery eyes, which are frequently combined with nasal and skin symptoms [1,2]
To determine the regulatory action of RvD2 on histamine-stimulated secretions, conjunctival goblet cell (CGC) derived from rats and humans were incubated with increasing concentrations of
RvD2 pre-treatment significantly decreased the H1induced [Ca2+ ]i increase to 121.1 ± 11.3 nM (p = 0.01). β-ARK1I treatment did not alter stimulation by H1 agonist, but reversed the inhibitory action of RvD2 on H1 agonist. These results indicate that RvD2 activates β-ARK1 to downregulate the H1 receptor subtype

Summary

Introduction

Allergic conjunctivitis is a predisposition to hypersensitivity reactions upon exposure to specific environmental antigens and is characterized by ocular symptoms, such as itching, blurry vision, redness, and watery eyes, which are frequently combined with nasal and skin symptoms [1,2]. This type of conjunctivitis has an estimated prevalence of 15–40%. Acute allergic conjunctivitis is treated with antihistamines or mast cell stabilizers. Both medications can effectively relieve ocular symptoms, but topical antihistamine therapy has a shorter duration and causes rebound hyperemia with continued use; topical mast cell stabilizers have a longer therapeutic effect but require a long loading period usually of days to weeks

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Conclusion