Please cite this article in press as: Burns, J.J., et al., The influence of traditional herbal formulas on cytokine activity. Toxicology (2009), doi:10.1016/j.tox.2009.09.020 ARTICLE IN PRESS G Model TOX-50424; No. of Pages 20 Toxicology xxx (2009) xxx–xxx Contents lists available at ScienceDirect Toxicology journal homepage: www.elsevier.com/locate/toxicol The influence of traditional herbal formulas on cytokine activity J.J. Burns a , Lijun Zhao b , Ethan Will Taylor b,c , Kevin Spelman c,d,* a Pinnacle Integrative Medicine, Phoenix, AZ, USA b Laboratory for Molecular Medicine, Office of Research, 206 Eberhart Bldg., University of North Carolina at Greensboro, Greensboro, NC 27402-6170, USA c Department of Chemistry & Biochemistry, University of North Carolina, P.O. Box 26170, 435 Science Building, Greensboro, NC 27402, USA d Department of Herbal Medicine, Tai Sophia Institute, Laurel, MD 20723, USA article info Article history: Received 28 June 2009 Received in revised form 24 September 2009 Accepted 29 September 2009 Available online xxx Keywords: Cytokine Herbal formula Immunomodulator Traditional medicine Interleukin (IL) Tumor necrosis factor (TNF) abstract Many of the botanical “immunomodulators”, a class of herbal medicines widely recognized in tradi- tional medical systems such as Chinese Medicine (TCM) and Ayurvedic Medicine, alter immune function and may offer clinically relevant therapeutics or leads to therapeutics. Many of these traditional reme- dies are prepared from combinations of medicinal plants which may influence numerous molecular pathways. These effects may differ from the sum of effects from the individual plants and therefore, research demonstrating the effects of the formula is crucial for insights into the effects of traditional remedies. In this review we surveyed the primary literature for research that focused on combinations of medicinal plants and effects on cytokine activity. The results demonstrate that many extracts of herb mixtures have effects on at least one cytokine. The most commonly studies cytokines were IL-4, IL-6, IL-10, TNF and IFN-. The majority of the formulas researched derived from TCM. The following formulas had activity on at least three cytokines; Chizukit N, CKBM, Daeganghwal-tang, Food Allergy Formula, Gamcho-Sasim-Tang, Hachimi-jio-gan, Herbkines, Hochuekki, Immune System Formula, Jeo-Dang-Tang, Juzen-taiho-to, Kakkon-to, Kan jang, Mao-Bushi-Saishin-to, MSSM-002, Ninjin-youei-to, PG201, Protec, Qing-huo-bai-du-yin, Qingfu Guanjieshu, Sambucol Active Defense, Seng-fu-tang, Shin-Xiao-Xiang, Tien Hsien, Thuja formula, Unkei-to, Vigconic, Wheeze-relief-formula, Xia-Bai-San, Yangyuk-Sanhwa-Tang, Yi-fey Ruenn-hou, and Yuldahansotang. Of the western based combinations, formulas with Echinacea spp. were common and showed multiple activities. Numerous formulas demonstrated activity on both gene and protein expression. The research demonstrates that the reviewed botanical formulas modulate cytokine activity, although the bulk of the research is in vitro. Therapeutic success using these formulas may be partially due to their effects on cytokines. Further study of phytotherapy on cytokine related diseases/syndromes is necessary. © 2009 Elsevier Ireland Ltd. All rights reserved. 1. Introduction Traditional herbal pharmacotherapy is well known for combin- ing plant species that results in complex phytochemical mixtures in the attempts to ameliorate pathophysiological processes. While research is necessary on isolated constituents and single herbal extracts to provide information about the molecular modes of activ- ity, such studies have limited relevance to the practical use of herbs due to the traditional custom of dispensing herbal medicine in for- mulas (Walker, 2006). The rationale for formulating suggest that the introduction of the complex mixture of chemistry into a human system provides not only pharmacologically active compounds, but concomitant compounds that are important to the therapeutic * Corresponding author. Present address: Tai Sophia Institute, 7750 Montpelier Road, Laurel, MD 20723, USA. Tel.: +1 410 888 9048/336 334 3832; fax: +1 410 888 9004/336 334 5402. E-mail address: phytochemks@gmail.com (K. Spelman). effect (Spelman et al., 2006b). Supporting this view are numerous studies that have established that pharmacokinetic potentiation by way of altered absorption, distribution, metabolism and elimina- tion is common place after ingestion of phytochemical mixtures. Wagner (2005) points out that herbs can be advantageous in treating pathophysiology due to their chemical complexity. For example, an additive effect can be expected if two bioactive sub- stances target the same pharmacological target, while a synergic activity commonly results if two or more compounds target differ- ent pharmacological sites (Wagner, 2005). Synergic effects have been estimated to increase activity 50–2000-fold compared to equivalent concentrations of a single compound (Tegos et al., 2002; Wagner, 2005). For example, rhein, an antimicrobial from Rheum officinale (Baill, Polygonaceae), potentiated bacterial killing up to 2000-fold when combined with a plant-based MDR efflux pump inhibitor (Tegos et al., 2002). Given that plants’ resistance to pests, including mam- malian herbivores, has been shown to be due to mix- tures of bioactive compounds (Dixon, 2001; Dyer et al., 0300-483X/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.tox.2009.09.020