Streptochlorin Suppresses Allergic Dermatitis and Mast Cell Activation via Regulation of Lyn/Fyn and Syk Signaling Pathways in Cellular and Mouse Models

Seung-Hwan Lee,Sushruta Koppula,Dong-Young Kim,Tae-Bong Kang,Sang-Kyu Ye,Hyung-Sik Won,Do-Wan Shim,Tack-Joong Kim,Kwang-Ho Lee,Hee Jae Shin,Irving Coy Allen

doi:10.1371/journal.pone.0074194

Seung-Hwan Lee, Sushruta Koppula + Show 9 more

Open Access

https://doi.org/10.1371/journal.pone.0074194

Copy DOI

Abstract

Allergic diseases are chronic inflammatory conditions with specific immune and inflammatory mechanisms. Scientific interest in understanding the mechanisms and discovering novel agents for the prevention and treatment of allergic disease is increasing. Streptochlorin, a small compound derived from marine actinomycete possesses anti-angiogenic and anti-tumor activities. However, the anti-allergic effects and underlying mechanisms remain to be elucidated. In the present study, we investigated the effect of streptochlorin on allergic responses in vitro and in vivo. Streptochlorin inhibited degranulation and production of tumor necrosis factor-α and IL-4 by antigen-stimulated mast cells. Streptochlorin also inhibited the phosphorylation of Akt and the mitogen-activated protein kinases (MAPKs), including p38, ERK, and JNK. Further, streptochlorin reduced the phosphorylation of Syk in RBL-2H3 cells and inhibited the activity of Lyn and Fyn. Furthermore, administration of streptochlorin suppressed the allergic reactions in both passive cutaneous anaphylaxis reaction and 2, 4-dinitrofluorobenzene (DNFB)-induced allergic dermatitis in mice model. Considering the data obtained, we report for the first time that streptochlorin possess anti-allergic properties. The underlying mechanism of streptochlorin in exhibiting potent anti-allergic activity might be through the inhibition of the Lyn/Fyn and Syk signaling pathways.

Highlights

Allergic diseases, including dermatitis, rhinitis, asthma, and eczema, can be triggered by a number of factors
We tested whether streptochlorin inhibited the antigen-stimulated degranulation in rat basophilic leukemia (RBL)-2H3 cells
Syk kinase is a key player in mast cell activation because it leads to the activation of several downstream signaling molecules, including phosphatidylinositol 3-kinase (PI3K), Akt, phospholipase Cc (PLCc), and major mitogen-activated protein kinases (MAPKs) [20,21]

Summary

Introduction

Allergic diseases, including dermatitis, rhinitis, asthma, and eczema, can be triggered by a number of factors. Initial signaling events from FceRI occupation involve coalescence of the aggregated receptors with specialized micro domains of the plasma membrane known as lipid rafts, activation of Src-family kinases and subsequently, tyrosine phosphorylation of the receptor subunits [5]. On the other side, following FceRI aggregation, the protein tyrosine kinase Fyn becomes activated, which results in tyrosine phosphorylation of the cytosolic adaptor molecule GAB2 (growthfactorreceptor-bound protein 2 (GRB2)-associated binding protein 2). This leads to the binding of phosphatidylinositol 3-kinase (PI3K) by GAB2, resulting in an increase in calcium (Ca2+)

Methods

Results

Conclusion