Modulation of Cytokine Expression
by Traditional Medicines:
A Review of Herbal Immunomodulators

This section is compiled by Frank M. Painter, D.C.
Send all comments or additions to:    Frankp@chiro.org

FROM:   Alternative Medicine Review 2006 (Jun); 11 (2): 128–150 ~ FULL TEXT

Kevin Spelman, MS; JJ Burns, ND; Douglas Nichols, ND; Nasha Winters, ND;
Steve Ottersberg, MS; Mark Tenborg, ND

Clinical Division,
Department of Herbal Medicine,
Tai Sophia Institute,
7750 Montpelier Road,
Laurel, MD 20723, USA.
spelman123@earthlink.net

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INTRODUCTION:   Modulation of cytokine secretion may offer novel approaches in the treatment of a variety of diseases. One strategy in the modulation of cytokine expression may be through the use of herbal medicines. A class of herbal medicines, known as immunomodulators, alters the activity of immune function through the dynamic regulation of informational molecules such as cytokines. This may offer an explanation of the effects of herbs on the immune system and other tissues. For this informal review, the authors surveyed the primary literature on medicinal plants and their effects on cytokine expression, taking special care to analyze research that utilized the multi-component extracts equivalent to or similar to what are used in traditional medicine, clinical phytotherapy, or in the marketplace.

METHODOLOGY:   MEDLINE, EBSCO, and BIOSIS were used to identify research on botanical medicines, in whole or standardized form, that act on cytokine activity through different models, i.e., in vivo (human and animal), ex vivo, or in vitro.

RESULTS:   Many medicinal plant extracts had effects on at least one cytokine. The most frequently studied cytokines were IL-1, IL-6, TNF, and IFN. Acalypha wilkesiana, Acanthopanax gracilistylus, Allium sativum, Ananus comosus, Cissampelos sympodialis, Coriolus versicolor, Curcuma longa, Echinacea purpurea, Grifola frondosa, Harpagophytum procumbens, Panax ginseng, Polygala tenuifolia, Poria cocos, Silybum marianum, Smilax glabra, Tinospora cordifolia, Uncaria tomentosa, and Withania somnifera demonstrate modulation of multiple cytokines.

CONCLUSION:   The in vitro and in vivo research demonstrates that the reviewed botanical medicines modulate the secretion of multiple cytokines. The reported therapeutic success of these plants by traditional cultures and modern clinicians may be partially due to their effects on cytokines. Phytotherapy offers a potential therapeutic modality for the treatment of many differing conditions involving cytokines. Given the activity demonstrated by many of the reviewed herbal medicines and the increasing awareness of the broad-spectrum effects of cytokines on autoimmune conditions and chronic degenerative processes, further study of phytotherapy for cytokine-related diseases and syndromes is warranted.

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From the FULL TEXT Article:

Introduction

Cytokines, a large group of soluble extracellular proteins or glycoproteins, are key intercellular regulators and mobilizers. Classified into family groups (e.g., interleukins, interferons, and chemokines) based on the structural homologies of their receptors, these proteins were initially believed to act primarily as antiviral1 or antineoplastic [2] agents. They are now seen to be crucial to innate and adaptive inflammatory responses, cell growth and differentiation, cell death, angiogenesis, and developmental as well as repair processes. [3] Their secretion, by virtually every nucleated cell type, is usually an inducible response to injurious stimuli. [3] In addition, cytokines provide a link between organ systems, providing molecular cues for maintaining physiological stability. [4] Medical literature of the last several decades reveals an array of conditions, from cardiovascular disease to frailty, whose onset and course may be influenced by cytokines. [5]

The diverse and far-reaching influences of these proteins can be seen in the central nervous system (CNS); cytokines cause the brain to produce neurochemical, neuroendocrine, neuroimmune, and behavioral shifts. [6] Abnormal cytokine production has been demonstrated in neuropsychiatric disorders such as attention deficit hyperactivity disorder, obsessive- compulsive disorder, and anorexia nervosa. [6, 7] Cytokines also appear to play a role in depression, schizophrenia, and Alzheimer’s disease, [7] and may be a common link between insomnia and depression. [8, 9] In addition, there appears to be an involvement of cytokines in anhedonia (the inability to experience pleasure) and learned helplessness. [10]

The understanding of stimuli that invoke cytokine secretion has expanded. Besides chronic infections, negative emotions and stressful experiences have been shown to stimulate production of proinflammatory cytokines. [5] In addition to involvement in neuropsychiatric disorders, these diverse glycoproteins have activity in all body systems. As models of physiology continue to develop beyond compartmentalized organ systems, elucidation of the global activity of cytokines offers further support to an expanding understanding of cell-to-cell communication. The inflammatory processes of cardiovascular disease are one such example. Beyond leukocytes, the liver, heart, vessel walls, and adipose tissue are known to produce cytokines; thus any of these tissues may potentially contribute to the inflammatory nature of cardiovascular disease. [11]

As a result of the growing recognition of cytokine activities, altering cytokine expression and targeting their receptors may offer therapeutic potential. Current pharmacological strategies include cytokine antagonist, agonist, inhibition, and stimulation models. [12] Therapeutic application of cytokines in clinical medicine has rapidly surpassed the FDA’s 1986 approval of an interferon (IFN) agonist for the treatment of hairy cell leukemia. In 2001, an antagonist to tumor necrosis factor (TNF), a pivotal cytokine in the pathogenesis of rheumatoid arthritis (RA), was described as one of the most important advances in RA treatment. [13] In addition, interleukin-1ß (IL-1ß) and TNF antagonists offer options for the treatment of periodontal disease. [14] A novel approach in the treatment of asthma is the inhibition of T-helper 2 (TH2) derived cytokine expression, resulting in downstream effects on IgE and eosinophils. [15] Interleukin-10 (IL- 10) demonstrates modulation of brain inflammation, which may have application for conditions such as Alzheimer’s disease. [16] In additional, interleukin-2 (IL-2) and interleukin-12 (IL-12) in combination may provide a potential therapeutic approach for neuroblastomas. [17]

Due to their diverse and pleiotropic activities, cytokine treatments may prove promising for disorders seemingly unrelated to immune function. However, much of their therapeutic effect relies on direct influence of immune activity. For example, in the field of oncology, progress has been made in the therapeutic use of several interleukins, including IL- 4, -6, -11 and -12. [18] In combination with surgery, pretreatment with IL-2 may enhance survival rates in patients with renal cell carcinoma. [19] IL-18 demonstrates antitumor effects in leukemia. [20] The interferons are used in the treatment of hepatitis B and C, malignant melanoma, follicular lymphoma, and AIDS-related Kaposi’s sarcoma. [21]

However, as with the development of many nascent pharmacological strategies, the occurrence of adverse events generates barriers to successful therapeutic applications. Such obstacles have delayed progress in the use of several synthetic cytokines. Treatment with recombinant cytokines has yielded a number of adverse effects, such as transient lymphopenias induced by IFN, IL-2, and TNF. Monocytopenia has been reported with the use of interferon- gamma (IFN-γ) and TNF, while IL-2, IFN-α, and TNF induce neutrophilia. [22] Patient experience of flu-like symptoms with the use of interferons makes adherence to a therapeutic protocol a challenge. Both IL-2 and IFN-α, used for the treatment of hepatitis C and some cancers, are known to evoke depression, fatigue, sleepiness, irritability, and loss of appetite. [23] These toxic side effects have limited the clinical value of such therapies. [24]

In light of the adverse events experienced with cytokine-targeted therapy, it could prove useful to consider the use of phytotherapy in the modulation of cytokine expression. Immune-related illnesses have long been treated with herbal medicines. The primary literature suggests many of the effects of botanicals may be via cytokine modulation. [25] The term immunomodulator has been used in the phytotherapy literature to describe botanical medicines believed to influence immunity. [26] In regard to phytotherapy, immunomodulators may be defined as botanical medicines that alter the activities of the immune system via the dynamic regulation of informational molecules – cytokines, hormones, neurotransmitters, and other peptides.

This article provides an informal review of the scientific literature regarding the effects of botanical medicines on cytokines. Islam and Carter point out that therapy based on medicinal plants, such as the immunomodulators, is based on diverse constituents or groups of constituents and therefore, researching isolated constituents to reveal modes of activity disregards the principles of phytotherapy. [27] In addition, when clinicians use medicinal plant preparations in practice, they often do not treat with isolated constituents. Therefore, in order to maintain relevance for clinical phytotherapy, this informal survey was limited to herbal medicines available in the marketplace or preparations that represent multi-component botanical medicines.

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