Effect of endocannabinoids on IgE-mediated allergic response in RBL-2H3 cells

• Published in: International immunopharmacology Vol. 17; no. 1; pp. 123 - 131
• Main Authors: Yoo, Jae-Myung, Sok, Dai-Eun, Kim, Mee Ree
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-09-2013
• Subjects: Allergic response; Animals; Anti-Allergic Agents - pharmacology; Endocannabinoids - pharmacology; Gene Expression Regulation - physiology; Immunoglobulin E - metabolism; LTB4; N-arachidonoyl serotonin; NADPH Oxidases; PGD2; Rats; RBL-2H3 cells; Receptors, IgE - genetics; Receptors, IgE - metabolism; Signal Transduction; PGD2; FAAH; 5-LO; COX-2; IgE; JNK; TNF; PI3K; HSA; LTB4; CB; NA-GABA; Lyn; TRPV; NA-5HT; Syk; NA-Ser; cPLA2; PKCδ; PLCγ; Allergic response; Akt; Gab2; N-arachidonoyl serotonin; NA-Tau; ERK1/2; 2-AG; NA-Gly; LTC4; RBL-2H3 cells; LAT; linker for activation of T cells; cyclooxygenase-2; GRB2-associated binding protein 2; transient receptor potential vanilloid; leukotriene C; leukotriene B; prostaglandin D; 2-arachidonoyl glycerol; c-Jun N-terminal kinase; spleen tyrosine kinase; N-arachidonoyl serine; PGD; cPLA; cytosolic phospholipase A; LTC; LTB; human serum albumin; N-arachidonoyl glycine; N-arachidonoyl γ-aminobutyric acid; phospholipase Cγ; cannabinoid; protein kinase Cδ; Immunoglobulin E; fatty acid amide hydrolase; 5-lipoxygenase; Src family protein kinase; extracellular signal-regulated kinase 1/2; protein kinase B; tumor necrosis factor; Phosphatidylinositol 3-kinase; N-arachidonoyl taurine
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2013.05.013

Recently, some endocannabinoids were reported to show anti-inflammatory and anti-allergic activities. In this respect, various arachidonoyl endocannabinoids were screened for the inhibition of allergic response in IgE-activated RBL-2H3 cells. Among arachidonoyl endocannabinoids with a low cytotoxicity, only NA-5HT remarkably inhibited the release of β-hexosaminidase (IC50, 13.58μM), a marker of degranulation, and tumor necrosis factor-α (IC50, 12.52μM), a pro-inflammatory cytokine, in IgE-activated RBL-2H3 cells. Additionally, NA-5HT markedly suppressed the formation of prostaglandin D2 (PGD2) with IC50 value of 1.27μM and leukotriene B4 (LTB4) with IC50 value of 1.20μM, and slightly LTC4. When effect of NA-5HT on early stage of FcεRI cascade was investigated, it significantly inhibited phosphorylation of Syk, but not Lyn. Furthermore, NA-5HT suppressed phosphorylation of PLCγ1/2 and PKCδ, related to degranulation process, as well as phosphorylation of LAT, ERK1/2, p38, JNK, Gab2, PI3K and Akt, implicated in the expression of pro-inflammatory cytokines. Relative to its effect on the late stage, NA-5HT slightly reduced phosphorylation of 5-lipoxygenase (5-LO) and cyclooxygenase-2 (COX-2). Additionally, NA-5HT significantly reduced the level of p40phox, and partially inhibited the expression of p47phox and p67phox. From these results, it is suggested that NA-5HT expresses anti-allergic action by suppressing the activation of Syk, LAT, p38, JNK, PI3K and Akt, as well as the expression of ERK1/2 and NADPH oxidase subunits. Further, a strong inhibition of PGD2 or LTB4 biosynthesis by NA-5HT may be an additional mechanism for its anti-allergic action. Such anti-allergic actions of NA-5HT may contribute to further information about its biological functions.
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•NA-5HT functions as a possible candidate of allergic therapy.•NA-5HT inhibited IgE-mediated degranulation in mast cells.•NA-5HT reduced IgE-induced formation of TNF-α, PGD2 and LTB4.•NA-5HT inhibited IgE-induced activation of FcεRI receptor cascade.•NA-5HT suppressed IgE-induced expression of NADPH oxidase.