Anti-Inflammatory and Pro-resolving Actions of the N-Terminal Peptides Ac2-26, Ac2-12 and Ac9-25 of Annexin A1 on Conjunctival Goblet Cell Function.

Annexin A1 (AnxA1) is the main mediator of the anti-inflammatory actions of glucocorticoids. AnxA1 functions as a pro-resolving mediator in cultured rat conjunctival goblet cells to ensure tissue homeostasis through stimulation of intracellular [Ca] ([Ca]) and mucin secretion. AnxA1 has several N-terminal peptides with anti-inflammatory properties of their own, including Ac2-26, Ac2-12 and Ac9-25. The increase in [Ca] caused by AnxA1 and its N-terminal peptides in goblet cells was measured to determine which formyl peptide receptors (FPRs) the compounds use and the action of the peptides on histamine stimulation. Changes in [Ca] were determined using a fluorescent Ca indicator. AnxA1 and its peptides each activated FPRs in goblet cells. AnxA1 and Ac2-26 at 10 M and Ac2-12 at 10 M inhibited the histamine-stimulated increase in [Ca] as did RvD1 and LXA at 10 M, while Ac9-25 did not. AnxA1 and Ac2-26 counter-regulated the H1 receptor through the p42p44MAPK/ERK1/2, β-adrenergic receptor kinase (βARK) and protein kinase C (PKC) pathways, whereas Ac2-12 counter-regulated only through βARK. In conclusion, the N-terminal peptides Ac2-26 and Ac2-12, but not Ac9-25, share multiple functions with the full-length AnxA1 in goblet cells, including inhibition of histamine-stimulated increase in [Ca] and counter-regulation of the H1 receptor. These actions suggest a potential pharmaceutical application of the AnxA1 N-terminal peptides Ac2-26 and Ac2-12 in homeostasis and ocular inflammatory diseases.