Resveratrol inhibits IL-33–mediated mast cell activation by targeting the MK2/3–PI3K/Akt axis

• Published in: Scientific reports 2019-12, Vol.9 (1), p.18423-11, Article 18423
• Main Authors: Nakajima, Shotaro, Ishimaru, Kayoko, Kobayashi, Anna, Yu, Guannan, Nakamura, Yuki, Oh-oka, Kyoko, Suzuki-Inoue, Katsue, Kono, Koji, Nakao, Atsuhito
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; 13/1; 13/109; 13/21; 13/31; 13/95; 631/250/2504/223/1324; 631/250/2504/223/1630; Administration, Intranasal; AKT protein; Allergic diseases; Animals; Basophils - drug effects; Basophils - immunology; Bone marrow; Cell activation; Cell Degranulation - drug effects; Cell Degranulation - immunology; Cells, Cultured; Cytokines; Degranulation; Disease Models, Animal; Fetuses; Histamine; Humanities and Social Sciences; Humans; Hypersensitivity - drug therapy; Hypersensitivity - immunology; Immunoglobulin E; Interleukin 13; Interleukin 6; Interleukin-1 Receptor-Like 1 Protein - antagonists & inhibitors; Interleukin-1 Receptor-Like 1 Protein - metabolism; Interleukin-33 - administration & dosage; Interleukin-33 - antagonists & inhibitors; Interleukin-33 - immunology; Intracellular Signaling Peptides and Proteins - antagonists & inhibitors; Intracellular Signaling Peptides and Proteins - metabolism; Intranasal administration; Kinases; Leukocytes (basophilic); Lung - immunology; Male; MAP kinase; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - immunology; Mast cells; Mast Cells - drug effects; Mast Cells - immunology; Mice; multidisciplinary; NF-κB protein; Phosphatidylinositol 3-Kinases - metabolism; Primary Cell Culture; Protein kinase; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Resveratrol; Resveratrol - pharmacology; Resveratrol - therapeutic use; Science; Science (multidisciplinary); Tumor necrosis factor-α
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-54878-5

Interleukin-33 (IL-33)/ST2–mediated mast cell activation plays important roles in the pathophysiology of allergic diseases. Hence, pharmacologically targeting the IL-33/ST2 pathway in mast cells could help to treat such diseases. We found that resveratrol inhibits IL-33/ST2–mediated mast cell activation. Resveratrol suppressed IL-33–induced IL-6, IL-13, and TNF-α production in mouse bone marrow–derived mast cells (BMMCs), mouse fetal skin–derived mast cells, and human basophils. Resveratrol also attenuated cytokine expression induced by intranasal administration of IL-33 in mouse lung. IL-33–mediated cytokine production in mast cells requires activation of the NF-κB and MAPK p38–MAPK-activated protein kinase-2/3 (MK2/3)–PI3K/Akt pathway, and resveratrol clearly inhibited IL-33–induced activation of the MK2/3–PI3K/Akt pathway, but not the NF-κB pathway, without affecting p38 in BMMCs. Importantly, resveratrol inhibited the kinase activity of MK2, and an MK2/3 inhibitor recapitulated the suppressive effects of resveratrol. Resveratrol and an MK2/3 inhibitor also inhibited IgE-dependent degranulation and cytokine production in BMMCs, concomitant with suppression of the MK2/3–PI3K/Akt pathway. These findings indicate that resveratrol inhibits both IL-33/ST2–mediated and IgE-dependent mast cell activation principally by targeting the MK2/3–PI3K/Akt axis downstream of p38. Thus, resveratrol may have potential for the prevention and treatment of broad ranges of allergic diseases.