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Ying Song,1,2,&ast; Zhen-Zhen Wang,1,3,&ast; Lixin Wang,4,&ast; Paul Faybusovich,2 Kamal Srivastava,3,5 Changda Liu,1,2 Jody Tversky,6 David Dunkin,7 Paula Busse,8 Xianqing Ren,9 Rachel Miller,8 Mingsan Miao,1 Xiu-Min Li3,10 1Academy of Chinese Medicine, Henan University of Chinese Medicine, Zhengzhou, People’s Republic of China; 2Department of Pediatrics, Division of Allergy and Immunology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 3Department of Pathology, Microbiology and Immunology, New York Medical College, Valhalla, NY, USA; 4Integrated TCM & Western Medicine Department, Shanghai Pulmonary Hospital Affiliated to Tongji University, Shanghai, People’s Republic of China; 5General Nutraceutical Technology LLC, Elmsford, NY, USA; 6The Department of Medicine, Division of Allergy and Clinical Immunology, Johns Hopkins Asthma and Allergy Center, Baltimore, Maryland, USA; 7Department of Pediatrics, Division of Gastroenterology and Nutrition, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 8Division of Clinical Immunology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 9The First Affiliated Hospital of Henan University of TCM, Zhengzhou, People’s Republic of China; 10Department of Otolaryngology, New York Medical College, Ardsley, NY, USA&ast;These authors contributed equally to this workCorrespondence: Xiu-Min LiProfessor of Pathology, Microbiology and Immunology, New York Medical College, Valhalla, NY Email XiuMin_Li@NYMC.eduBackground: It has been demonstrated that ASHMI (antiasthma-simplified herbal medicine intervention) can improve airway function and reduce inflammation in human asthmatic patients with high safety and tolerability. In addition, ASHMI significantly suppresses Th2 cytokine production and increases Th1 cytokine production in treating asthma.Objective: Allergic asthma is associated with dysregulation of cytokines. We focused on IL-5 and IL-10 as signature Th2 and Treg cytokines to characterize ASHMI immunomodulatory components.Methods: The effects of ASHMI and individual herbal constituents on IL-5 and IL-10 production by PBMCs from asthmatic subjects were determined ex vivo. Sophora flavescens (SF)-F2, containing alkaloid compounds, effects on PBMC IL-10 and IL-5 production in the presence or absence of dexamethasone (Dex), and on DNA methylation levels at the foxp3 gene promoter were determined.Results: The ratio of anti-CD3/CD28 stimulated IL-10/IL-5 production by PBMCs from asthmatic subjects was significantly reduced compared to healthy subjects. In PBMCs from asthmatic subjects, ASHMI significantly reduced IL-5 production and increased IL-10 secretion in a dose-dependent manner (p < 0.05– 0.01). SF-F2 was most effective in increasing IL-10, whereas SF-F4 (flavonoid compounds) was most effective in suppressing IL-5 production. Dex-treated PBMCs from asthma subjects showed a trend of increasing ratio of IL-10/IL-5 while demonstrating reduced levels in both IL-5 and IL-10 (p < 0.05). Co-culture with Dex and SF-F2 significantly prevented Dex suppression of IL-10, while retained Dex-suppression of IL-5 production, and increased IL-10/IL-5 ratio by Dex. Co-culture with SF-F2 and Dex significantly reduced DNA methylation levels at the foxp3 gene promoter at CpG− 126.Conclusion: The SF alkaloid-rich fraction may be responsible for ASHMI induction of IL-10 production by PBMCs and plays a synergistic effect with Dex for augmenting IL-10/IL-5 ratio.Keywords: Sophora flavescens, IL-10/IL-5 ratio, asthma, foxp3 methylation, synergistic effect