Clinical Reviews in Allergy & Immunology

, Volume 44, Issue 3, pp 284–300

Scientific Basis of Botanical Medicine as Alternative Remedies for Rheumatoid Arthritis

Authors

  • Cindy L. H. Yang
    • Molecular Chinese Medicine Laboratory, Li Ka Shing Faculty of MedicineThe University of Hong Kong
  • Terry C. T. Or
    • Molecular Chinese Medicine Laboratory, Li Ka Shing Faculty of MedicineThe University of Hong Kong
    • Department of Paediatrics and Adolescent MedicineThe University of Hong Kong
  • Marco H. K. Ho
    • Department of Paediatrics and Adolescent MedicineThe University of Hong Kong
    • Molecular Chinese Medicine Laboratory, Li Ka Shing Faculty of MedicineThe University of Hong Kong
    • Department of Paediatrics and Adolescent MedicineThe University of Hong Kong
Article

DOI: 10.1007/s12016-012-8329-8

Cite this article as:
Yang, C.L.H., Or, T.C.T., Ho, M.H.K. et al. Clinic Rev Allerg Immunol (2013) 44: 284. doi:10.1007/s12016-012-8329-8

Abstract

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune inflammatory disorder that causes permanent disability and mortality to approximately 1 to 100 people in the world. Patients with RA not only suffer from pain, stiffness, swelling, and loss of function in their joints, but also have a higher risk of cardiovascular disease and lymphoma. Typically prescribed medications, including pain-relieving drugs, nonsteroidal anti-inflammatory drugs (NSAID), and disease-modifying antirheumatic drugs, can help to relieve pain, reduce inflammation and slow the course of disease progression in RA patients. However, the general effectiveness of the drugs has been far from satisfactory. Other therapeutic modalities like TNF-alpha (TNF-α) inhibitors and interleukin-1 receptor antagonists targeting precise pathways within the immune system are expensive and may be associated with serious side effects. Recently, botanical medicines have become popular as alternative remedies as they are believed to be efficacious, safe and have over a thousand years experience in treating patients. In this review, we will summarize recent evidence for pharmacological effects of herbs including Black cohosh, Angelica sinensis, Licorice, Tripterygium wilfordii, Centella asiatica, and Urtica dioica. Scientific research has demonstrated that these herbs have strong anti-inflammatory and anti-arthritic effects. A wide range of phytochemicals including phenolic acids, phenylpropanoid ester, triterpene glycosides, phthalide, flavonoids, triterpenoid saponin, diterpene and triterpene have been isolated and demonstrated to be responsible for the biological effects of the herbs. Understanding the mechanisms of action of the herbs may provide new treatment opportunities for RA patients.

Keywords

Rheumatoid arthritisMediatorsBlack cohoshAngelica sinensisLicoriceTripterygium wilfordiiCentella asiaticaUrtica dioica

Introduction

Rheumatoid arthritis (RA) is the most common inflammatory arthritis and is a major cause of disability. About 1 % of the world's population is afflicted by RA, and it occurs in women three times more often than men. Onset is most frequent between the ages of 40 and 50, but people of any age can be affected. It is a clinical diagnosis made on the basis of symptoms, physical examinations, radiographs and relevant laboratory results.

RA typically manifests with signs of inflammation, with the affected joints being swollen, warm, painful and stiff, particularly early in the morning on waking or following prolonged inactivity. With time, RA nearly always affects multiple joints, most commonly small joints of the hands, feet and cervical spine, but larger joints like the shoulder and knee can also be involved. The joints are often affected in a fairly symmetrical fashion. As the pathology progresses the inflammatory activity leads to tendon tethering and erosion and destruction of the joint surface, which impairs the range of movement and leads to deformity.

Co-morbidities and extra-articular features are common up to 50 %, though severe extra-articular complications such as vasculitis, pericarditis, pleuritis, and/or Felty's syndrome occur in less than 10 % of patients [1]. Extraarticular disease is the major predictor of mortality in patients with RA [1]. Recent cohort studies seem to show much less vasculitis than earlier studies [1] which might be a reflection of recent advances in effective therapy.

The 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) RA classification focuses on features at earlier stages of disease that are associated with persistent and/or erosive disease, rather than defining the disease by its late-stage features [2].

Effects of Mediators on the Progression of RA

  1. 1.

    Tumor Necrosis Factor (TNF-α)

     
TNF-α, a proinflammatory macrophage-derivated cytokine, is present in high concentration in the synovial fluid of patients with RA [3] during the early stages of disease. It plays a central role in the pathogenesis of RA as it amplifies inflammation and causes joint damage. On the one hand, TNF-α is an autocrine stimulator as well as a potent paracrine inducer of proinflammatory mediators including interleukin 1 (IL-1) [4], IL-6 [5], IL-8 [5] and granulocyte-macrophage colony-stimulating factor (GM-CSF) [6]. It also stimulates synovial fibroblasts to express intercellular adhesion molecule 1 which increases the migration of leukocytes into the RA joints [7]. Additionally, TNF-α stimulates chondrocytes to release matrix metalloproteinases (MMPs) which degrade components of cartilage, bone and tendons in the joints, [8] and inhibits the production of tissue inhibitors of metalloproteinases (TIMPs) by synovial fibroblasts [9]. Furthermore, TNF-α can also induce nitric oxide production and release prostaglandin E2 (PGE2) by synovial cells, which in turn causes tissue destruction [10]. With the treatment of RA using TNF-α inhibitors, the production of proinflammatory cytokines and the development of arthritis have been reduced [11].
  1. 2.

    Interleukin 1 (IL-1)

     
IL-1 is another key mediator involved in bone resorption and cartilage destruction in RA. Patients with RA have higher IL-1 concentrations in their plasma and synovial fluid than do healthy individuals [12]. Local levels remained high long after the onset of RA. Similar to TNF-α, IL-1 increases the production of MMPs by chondrocytes, which in turn causes the joint damage in patients with RA [8]. In addition to MMPs, IL-1 is the key cytokine involved in modulating the production of nitric oxide and PGE2 from activated chondrocytes. These mediators have been shown to contribute to the progression of disease in RA patients [13].
  1. 3.

    Interleukin 17 (IL-17)

     
Elevated levels of IL-17, a pro-inflammatory Th17-cell derived cytokine, have been detected in the synovial fluid of patients with RA [14]. Numerous studies have demonstrated the important role of IL-17 in the joint inflammation in RA patients, through its interaction with synovial tissue fibroblasts and macrophages to induce the production of IL-1, TNF-α, IL-6, IL-8, and macrophage inflammatory protein-1α (MIP-1α) [15]. IL-17 also plays a significant role in the induction of cartilage destruction in RA through the production of nitric oxide and PGE2 [16], from which it displays considerable synergism with TNF-α and IL-1[16]. IL-17 also induces the production of MMP-9 that is highly specific for degrading denatured collagen (gelatin) [17]. Furthermore, IL-17 induces arthritis by mediating the migration of endothelial cells and tube formation in RA [18].
  1. 4.

    Matrix Metalloproteinases (MMPs)

     
MMPs, secreted by cytokine-stimulated cells, have been detected in serum, synovial fluid and synovial tissue as well as the sites of cartilage erosion of RA patients [19]. MMPs can be classified into at least five main categories including the collagenases, gelatinases, stromelysins, matrilysins and membrane type-MMPs. Activated MMPs are capable of cleaving cartilage extracellular matrix (ECM) [20]. For instance, the collagenase of MMP-13 hydrolyses type II collagen [21] and aggrecan at specific sites [22]. The stromelysin of MMP-3 cleaves proteoglycans, collagens, gelatins, laminin, fibronectin [23] and link protein of aggrecan [24]. Furthermore, gelatinase B (MMP-9) degrades the fibrillar collagens, gelatins, basement membrane components and fibronectin. Therefore, joint destruction may be preventable by inhibiting the activities of pathogenic MMPs [25].
  1. 5.

    Prostaglandin E2 (PGE2)

     
High levels of the pro-inflammatory prostaglandin, PGE2, has been detected in human joint fluid and synovial tissue of RA patients [26]. The inflammatory actions of PGE2 include sensitizing pain receptors and inducing fever [27]. It enhances IL-17 production, and reduces IL-12 and IFN-γ production, leading to the migration of neutrophils into the affected joints [28]. Moreover, it promotes neovascularization of the joint by stimulating the production of vascular endothelial growth factor (VEGF) [29]. In addition, the effects of IL-1, IL-6 and TNF-α on bone resorption have been shown to be PGE2 dependent [30].
  1. 6.

    Nitric Oxide

     

Nitric oxide has been reported to be an important mediator in the progression of cartilage and bone destruction in RA [31]. It can induce the production of pathogenic cytokines (TNF-α) and chemokines (macrophage inflammatory protein) which contribute to the progression of arthritis [32]. Moreover, nitric oxide activates MMPs and inactivates TIMPs production. It promotes vasodilatation, which leads to fluid and cellular influx into an inflammatory site [33]. Nitric oxide also reacts with reactive oxygen species to produce peroxynitrite, which promotes the apoptosis of chondrocytes [33]. Furthermore, nitric oxide derived from iNOS may act as a mediator of cytokine-induced bone resorption [34].

Roles of Macrophages, B Cells, Dendritic Cells and T Cells in the Pathogenesis of RA

Macrophages, B cells and T cells accumulate in the inflamed synovial membrane and at the cartilage–pannus junction of RA patients [35]. The infiltration of macrophages into the synovium plays a pivotal role in the pathogenesis and severity of RA [36]. In response to pathogens and cytokines, stimulated macrophages produce a wide variety of proinflammatory cytokines (mainly IL-1 and TNF-α) and chemokines (IL-8), which amplify and propagate the inflammation process and cause further joint damage [37]. Macrophages can also interact with other synovial-tissue cells (T cells and fibroblasts) to produce cytokines in the absence of stimuli. These inflammatory mediators then induce the expression of MMPs to degrade collagens in the cartilage and bone, which ultimately leads to joint damage [38].

B cells are lymphocytes that play a crucial role in the progression of RA through multiple mechanisms. They produce autoantibodies such as rheumatoid factor (RF) and anti-cyclic-citrullinated peptide (anti-CCP), which contribute to immune complex formation and complement activation in the joints [39]. B cells are the primary source of receptor activator of nuclear factor-kappaB ligand (RANKL), which is a key mediator of joint destruction and bone loss in adjuvant arthritis [40]. In addition, B cells also secrete multiple cytokines in the synovial environment, including lymphotoxin α (LTα), TNF-α and IL-1, that perpetuate the inflammatory process.

Macrophages, dendritic cells and B cells are antigen presenting cells that express both class II major-histocompatibility-complex (MHC) and costimulatory molecules, leading to activation of T cells. These represent a large proportion of the inflammatory cells invading the synovial tissue. Direct contact between T cells and fibroblasts or between T cells and macrophages can enhance the production of cytokines [41], MMPs [42], and PGE2 [42]. CD4+ and CD45RO + T cells mainly account for the persistence of synovitis in RA. CD4+ T cells can be divided into Th1 and Th2 cells. Th1 cells produce proinflammatory cytokines including IL-2, IFN-γ and TNF-α, leading to macrophage activation, whereas Th2 cells down-regulate macrophage activation through the secretion of anti-inflammatory cytokines IL-4, IL-5, and IL-10. The development of RA has been associated with an imbalance in Th1/Th2 cells. In RA, Th1 cells predominate leading to production of pro-inflammatory mediators [43]. The CD4+ T cell subset Th17 cells produce IL-17 which is thought to contribute to the inflammation associated with RA [44].

Cell Signaling Pathways and Transcription Factors Involved in Arthritis

Three major mammalian MAP kinases, including the extracellular signal-regulated kinase (ERK), the c-Jun N-terminal kinase (JNK), and p38 kinase, are expressed in the synovial tissue of RA patients [45]. In response to inflammatory stimuli, mitogen-activated protein (MAP) kinases are activated to enhance the expression of MMPs [46, 47] and the proinflammatory cytokines TNF-α, IL-1β and IL-6 [45]. Inhibition of p38 MAPK has been shown to suppress paw swelling, joint damage and the production of inflammatory cytokines.

In RA, the transcription factor nuclear factor-kappaB (NF-κB) is overexpressed in the inflamed synovium [48]. It participates in the transactivation of various genes for cytokines, chemokines, adhesion molecules, MMPs [49], COX-2 [50], and inducible nitric oxide (iNOS) [51], which mediate immune and inflammatory responses [52]. It can activate and be activated by IL-1β and TNF-α, resulting in a positive regulatory loop, which leads to amplification of local inflammatory responses.

Existing Drugs for Treating RA

Conventionally, pharmacological treatments of RA consist of NSAID (non-steroidal anti-inflammatory drug) and steroids for controlling symptoms, while disease-modifying antirheumatic drugs (DMARDs) (e.g., methotrexate (MTX), suphazalazine, and leflunomide) inhibit or halt the underlying immune process and prevent long-term damage. But the overall effect has been far from satisfactory. In recent times, specific therapeutic interventions can be designed, based on knowledge of pathogenesis, to suppress synovial inflammation and joint destruction in RA.

The advent of tumor necrosis factor (TNF) inhibitors [53] illustrates the success of applied translational research in RA. Their development was based on characterization of cytokine networks and studies suggesting that TNF-α production might serve as an autologous stimulus for other cytokines in RA synovium [54]. Treatment with TNF inhibitors plus MTX, but not MTX monotherapy alone, inhibits joint damage progression even at higher levels of disease activity. The latest EULAR (European League Against Rheumatism) treatment recommendations for RA promote new treatment strategies including early use of new biologic modulator therapy, tight symptom control and rapid switching of medications [55].

About 40 % of patients have dramatic responses to TNF inhibitors, but the remaining patients have some evidence of persistent synovitis or minimal clinical benefit, demonstrating the need for other treatment modalities. IL-1Ra, a natural IL-1 antagonist, was approved by the United States Food and Drug Administration (FDA) for RA patients who have failed one or more DMARDs (Disease modifying antirheumatic drugs) therapy. IL-1Ra can be used alone or in combination with DMARDs other than TNF inhibitors. The response rates are less than that of TNF inhibitors, likely because IL-1Ra is a competitive antagonist that must be present in large excess. Several additional cytokine-directed agents, such as anti-IL-6 receptor antibody, are also in clinical development, with preliminary response rates comparable to those treated with TNF antagonists [56].

The role of auto-antibodies in the pathogenesis of RA raises the possibility that B-cell specific therapy might be useful in RA. Rituximab, which targets CD20, seems to be effective in RA in human trials, especially in combination with cyclophosphamide, methotrexate and/or corticosteroids [57].

Herbs that are Well-Known for Treating RA

Botanical medicines have been used as alternative remedies for treating various diseases as they are believed to be efficacious, safe and have been used in various cultures to treat patients for thousands of years. In this review, we will summarize recent research of six herbs including Black cohosh, Angelica sinensis, Licorice, Tripterygium wilfordii, Centella asiatica, and Urtica dioica and their chemical components (Fig. 1), all of which are known alternative medicine treatments of RA. The in vitro and in vivo pharmacological effects of these herbs are summarized in Tables 1 and 2 and Figs. 2 and 3.
Table 1

Summary of the pharmacological effects of herbs

Black cohosh (BC)

In vitro/ ex vivo

   

Cells used

Inducer(s)

Functions

Mechanisms

References

Human whole blood

LPS

↓ IL-6 , IFN-γ and TNF-α production

↓ mRNA levels of IL-6 , IFN-γ and TNF-α

[61]

RAW 264.7 cells

LPS/TNF-α

↓ TNF-α and MIP-2 production

Nil

[62]

RAW264.7 cells

Influenza virus

↓ IL-8 production

Nil

[63]

Primary blood macrophages

LPS

↓ TNF-α production

↓ ERK and NF-κB activation

[60]

RAW 264.7 cells

LPS

↓ NO production

↓ iNOS mRNA levels

[59]

RAW 264.7 cells

LPS

Nil

↓ COX-2 gene expression

[64]

Bone marrow macrophages

RANKL/TNF-α

↓ osteoclast differentiation

↓ ERK and NF-κB activation

[65]

Black cohosh

In vivo

   

Type of animals/Human

Disease model used

Functions

Mechanisms

References

Rats

Carrageenan

↓ paw edema

Nil

[66]

Mice

TNF-α

↓ bone resorption

Nil

[65]

Patients with RA

Nil

↓ chronic arthritis pain

Nil

[67, 68]

changing in modified Ritchie articular index

Angelica sinensis (AS)

In vitro/ ex vivo

   

Cells used

Inducer(s)

Functions

Mechanisms

References

RAW 264.7 cell

UHMWPE

↓ TNF-α and IL-1β production

Nil

[73]

BALB/c mice peritoneal macrophages

LPS/IFN-γ

↓ secretion of NO and PGE2

↓ NF-κB transactivation activity

[72]

RAW 264.7 cells

LPS/IFN-γ

↓ TNF-α, IL-6, and MIP-2 production

↓ NF-κB luciferase activity

[74, 75]

↓secretion of NO and PGE2

 

Murine DC 2.4 cells

LPS

↓ TNF-α and IL-6 production

↓ NF-κB transactivation activity

[76]

Chondrocytes

H2O2

↓ IL-1β, TNF-α, MMP-1 and MMP-13 mRNA level

Nil

[70]

Angelica sinensis (AS)

In vivo

   

Type of animals

Disease model used

Functions

Mechanisms

References

C57BL/J6 mice

UHMWPE

↓ TNF-α and IL-1β production

Nil

[73]

↓ osteolysis area and number of osteoclasts

BALB/c mice

LPS

↑ survival rate

↓ NF-κB luciferase activity

[74]

↓ TNF-α and IL-12p40 levels

 

BALB/c mice

MSU crystals

↓ immigration of neutrophil

↓ IL-6 and TNF-α mRNA levels

[81]

Licorice (LR)

In vitro/ ex vivo

   

Cells used

Inducer(s)

Functions

Mechanisms

References

J774A.1 murine macrophages

LPS

↓ NO, IL-1β, IL-6, and PGE2 production

Nil

[88, 89]

RAW264.7 cells

LPS

↓ IL-1β, IL-6, TNF-α, NO and PGE2 production

↓ NF-κB activation

[9093]

THP-1 cell

LPS-IFN-γ

Nil

↓ iNOS expression and activity via NF-κB

[95]

Licorice (LR)

In vitro/ ex vivo

   

Type of animals

Disease model used

Functions

Mechanisms

References

Rats

Carrageenan

↓ paw edema

Nil

[96]

Mice

LPS

↑ survival rate

Nil

[90]

↑ IL-10 production

↓ IL-6 and TNF-α production

Mice

CIA

↓ arthritis score and paw edema

↓ MMP-3 expression

[97]

↓ IL-1β and TNF-α production

 

Mice

TPA

↓ ear edema

Nil

[97]

Adrenalectomized rats

Formaldehyde

↓ paw edema

Nil

[98]

Rats

CIA

↓ arthritic index

↓ TNF-α level

[99]

Tripterygium wilfordii (TW)

In vitro/ ex vivo

   

Cells used

Inducer(s)

Functions

Mechanisms

References

Primary human synovial cells

IL-1β

↓ PGE2 production

↓ COX-2 mRNA and protein

[107]

↓ NF-κB activity

Primary human T cells

Different antigens and mitogens

↓ proliferation of T-cells

↓ IL-2 production

[105]

Human peripheral blood fibroblasts, human neonatal, foreskin fibroblasts

LPS

↓ PGE2 production

↓ COX-2 mRNA

[108]

Murine RAW264.7 macrophage cells

LPS

↓ nitric oxide production in LPS-stimulated cells

↓ NF-κB gene expression

[104]

↑ nitric oxide production in untreated cells

Primary human femoral head osteoarthritic chondrocytes, normal bovine chondrocytes

TNF-α

↓ MMP-3 and MMP-13 production

↓ DNA binding capacity of AP-1 and NF-κB

[110]

IL-1

IL-17

Tripterygium wilfordii

    

(TW)

In vivo

   

Type of animals

Disease model used

Functions

Mechanisms

References

Rats

Streptococcal cell wall/ adjuvant

↓ joint swelling and structural damage

Nil

[111]

Rats

Adjuvants

↓ joint edema

Nil

[112]

Rats

Carrageenan

↓ PGE2, nitric oxide and TNF-α production

↓ COX-2 mRNA

[113]

Mice

Type II collagen

↓ arthritis incidence

Nil

[114]

↑ day of onset

↓ arthritic joint counts, arthritic severity scores, and anticollagen antibody titers

Centella asiatica (CA)

In vivo

   

Type of animals

Disease model used

Functions

Mechanisms

References

Rats

Carageenan

↓ oedema volume

Nil

[136]

Rats

Acetic acid induced ulcer

↓ nitric oxide

↓ iNOS activity

[135]

Rats

Hydrogen peroxide

↓ malonaldehyde (MDA) level in blood

Nil

[138]

↓ superoxide dismutase (SOD) activity

Rats

PGE2 induced edema

↓ paw edema

Nil

[137]

Urtica dioica (UD)

In vitro/ex vivo

   

Cells used

Inducer(s)

Functions

Mechanisms

References

Human whole blood

LPS

↓TNF-α, IL-1β levels

Nil

[146]

Human epithelial cell line hela

TNF-α

↓ NF-κB-DNA binding

Nil

[149]

↓ NF-κB reported gene expression

↓ IκB degradation

Human primary chondrocytes

IL-1β

↓ MMP-1, -3 and -9 proteins

Nil

[152]

Primary mouse peritoneal macrophages

LPS

↓ nitric oxide production

Nil

[147]

Primary Human dendritic cells

Nil

↓ % of CD-83 and CD-86 + dendritic cells

Nil

[151]

 

↑ CCR-5 and CD-36 + dendritic cells

Keyhole limped hemocyanin (KLH)

↓ TNF-α production

Table 2

Summary of the pharmacological effects of compounds

Triptolide (TP)

In vitro/ex vivo

   

Cells used

Inducer(s)

Functions

Mechanisms

References

Primary murine bone marrow derived dendritic cells

LPS

↓ Chemoattraction of neutrophils and T cells

↓ NF-κB activation

[119]

↓ MIP-1α, MIP-1β, MCP-1, RANTES, TARC, and IP-10

↓ Stat3 phosphorylation

 

↑ SOCS1 expression

Primary human peripheral blood Mononuclear cells

Superantigen (TSST-1) Staphylococcal Exotoxins (SE) / lipopolysaccharide (LPS)

↓ IL-1β, IL-6, TNF-α, IFNγ, MCP-1, MIP-1α, MIP-1β

↓ TNF-α, IL-1β, IL-8, IFNγ, IP-10, MIP-1α, MIP-1β, and MCP-1 gene expressions

[117]

↓ T-cell proliferation

Primary human rheumatoid arthritis synovial fibroblasts

Phorbol 12-myristate 13-acetate (PMA)

↓ IL-18 and IL-18R protein and mRNA levels

↓ NF-κB activity

[122]

Primary murine splenocytes

Anti-CD3

↓ IL-17 production

 

[120]

CD4+ T-cells

IL-6 + TGF-β

↓ IL-17 gene expressions

↓ IL-17 production

  

↓ nitric oxide production

↓ STAT-3 phosphorylation

Primary murine peritoneal macrophages

LPS

↓ nitric oxide production

↓ iNOS protein and mRNA levels

[102]

Human chondrosarcoma cell line, SW1353/ Primary human knee synovial fibroblasts

IL-1β/ TNFα

↓ MMP-3 and MMP-13 gene expression

Nil

[123]

Primary bovine chondrocytes

IL-1β/ IL-17/ TNF-α

↓ Aggrecanase-1 gene expression

Nil

Primary human synovial fibroblasts

IL-1α

↓ proMMPs 1 and 3 production

↓ proMMPs 1 and 3 gene expression

[118]

Murine macrophages J774A

LPS

↓ PGE2 production

↓ COX-2 protein and gene expression

[118]

↓ IL-1α, IL-1β, TNF-α, and IL-6 gene expression

Nil

Triptolide (TP)

In vivo

   

Type of animals

Disease model used

Functions

Mechanisms

References

Rats

Type II collagen

↓ arthritic score

Nil

[124]

↑ onset of arthritis

↓ CD4+ cells in Peyer’s patch

Rats

Type II collagen

↓ arthritic scores

Nil

[129]

↓ CD4+ cells in periphery

↓ CD4+ and CD8+ cells in Peyer’s patch

↑ TGF-β

↓ IFN-γ

Rats

Type II collagen

↓ histological damage and cumulative arthritis injury scores

↓ IL-1β, IL-6 and TNF-α mRNA levels

[130]

↓ MMP-3 and 13 levels

 

↑ TIMP-1 and 2

↓ COX-2 production

↓ PGE2

↓ NF-κB protein and mRNA levels

Mice

Type II collagen

↓ arthritic score

↓ CD8+ T cells in Peyer’s patch

[125]

↑ TGF-β

↓ CD8+ T cells in intraepithelial lymphocytes

Rats

Type II collagen

↑ onset of arthritis

Nil

[126]

 

↓ arthritis incidence

 

↓ clinical and histopathological arthritis severity score

Madecassoside

In vitro/ex vivo

   

Cells used

Inducer(s)

Functions

Mechanisms

References

Murine RAW264.7 macrophages

LPS

↓ nitric oxide, PGE2,

↓ protein levels of iNOS and COX-2

[140]

TNF-α, IL-1β, and IL-6

↓ mRNA levels of iNOS, COX-2, TNF-α, IL-1β, and IL-6

 

↓ NF-κB − DNA binding

Madecassoside

In vivo

   

Type of animals

Disease model used

Functions

Mechanisms

References

Mice

Type II collagen

↓ clinical scores

Nil

[141]

↑ body weights’

↓ infiltration of inflammatory cells and synovial hyperplasia

↓ serum level of anti-CII IgG

↓ delayed type hypersensitivity

↓ proliferation of lymphocytes

Mice

Type II collagen

↓ hind paw volume

↓ production of PGE2 and COX-2 expression

[142]

↓ arthritic score

↓ plasma level of TNF-α and IL-6

↓ proliferation of T-cells in spleen

↑ plasma level of IL-10

https://static-content.springer.com/image/art%3A10.1007%2Fs12016-012-8329-8/MediaObjects/12016_2012_8329_Fig1_HTML.gif
Fig. 1

The chemical structures of bioactive compounds isolated from herbs. [1] isoferulic acid; [2] ferulic acid; [3] cimiracemate A; [4] 23-epi-26-deoxyactein; [5] 25-acetylcimigenol xylopyranoside; [6] salicylic acid; [7] Z-ligustilide; [8] n-Butylidenephthalide; [9] glabridin; [10] isoliquiritigenin; [11] liquiritigenin; [12] glycyrol; [13] licochalcone C; [14] glycyrrhizin; [115] licochalcone A; [16] triptolide; [17] madecassoside

https://static-content.springer.com/image/art%3A10.1007%2Fs12016-012-8329-8/MediaObjects/12016_2012_8329_Fig2_HTML.gif
Fig. 2

Summary of the inhibitory effects of different medicinal herbs on the signaling pathways involved in inflammatory responses of the cell in rheumatoid arthritis. BC: black cohosh; AS: Angelica sinensis; TW: Tripterygium wilfordii; UD: Urtica dioica; LR: Licorice

https://static-content.springer.com/image/art%3A10.1007%2Fs12016-012-8329-8/MediaObjects/12016_2012_8329_Fig3_HTML.gif
Fig. 3

Summary of the inhibitory effects of different medicinal herbs on T-cells interactions during rheumatoid arthritis. CA: Centella asiatica; TW: Tripterygium wilfordii; UD: Urtica dioica

  1. 1.

    Black Cohosh (BC)

     

BC, also known as Actaea racemosa or Cimicifuga racemosa, was first recorded in the U.S. Pharmacopoeia in 1830 [58]. It has been used in the treatment of rheumatism, arthritis, fatigue, malaria, colds, and gynecological and kidney disorders by native American Indians for many years [58]. Its counterparts, including Cimicifuga dahurica, C. foetida, C. heracleifolia and C. simplex, have been used in the treatment of fever, pain and inflammation in Asian countries. Today BC is gaining popularity as the principal herbal remedy for menopausal symptoms in Europe and North America.

The roots and rhizomes of BC contain three major classes of chemical constituents including triterpene glycosides, phenylpropanoid derivatives, and flavonoids. These have been associated with the biological functions of BC [59, 60]. In vitro, extracts of the roots of BC have been shown to reduce lipopolysaccharide (LPS)-stimulated IL-6, TNF-α and IFN-γ production in human whole blood. Isoferulic acid has been shown to be responsible for anti-inflammatory effects [61]. The isomer of isoferulic acid, ferulic acid, also exerts anti-inflammatory activity by inhibiting TNF-α and macrophage inflammatory protein-2 (MIP-2) production in LPS-induced RAW 264.7 cells [62]. Both of the compounds inhibit the production of chemokine (IL-8) in response to influenza virus infections in RAW 264.7 cells [63]. Our previous study investigated the anti-inflammatory effect of BC and its bioactive compounds in LPS-induced TNF-α production in primary blood macrophages [60]. Results revealed that cimiracemate A, one of the most potent compounds in BC, suppressed LPS-induced TNF-α production in the blood macrophages by inhibiting ERK and NF-κB pathways [60].

BC not only inhibits the production of proinflammatory cytokines, but also alters the expression of other biochemical mediators including iNOS and COX-2 [59, 64]. Studies demonstrated that BC extracts reduced nitric oxide production by inhibiting iNOS mRNA levels and protein expression in LPS-induced Raw 264.7 cells. 23-epi-26-deoxyactein was shown to be the major active compound in BC [59]. Isoferulic acid also showed potent inhibition of COX-2 expression in LPS-induced RAW 264.7 cells without cytotoxicity [64]. In addition, a triterpenoid glycoside, 25-acetylcimigenol xylopyranoside (ACCX) isolated from BC, can block RANKL or TNF-α –induced bone loss in vitro. This effect may also be due to the inhibition of the NF-κB and ERK pathways [65].

In vivo, ferulic acid has been shown to reduce inflammation in carrageenan-induced rat paw edema [66]. The efficacy of ACCX on suppression of cytokine induced bone loss has been demonstrated in vivo as well. Mice injected with ACCX had significantly lower extent of bone loss induced by TNF-α [65]. BC contains small amounts of salicylic acid, which is well known for relieving pain caused by RA. Reumalex®, a commercialized herbal medicine containing BC, has been shown to help reduce chronic arthritis pain in RA patients [67]. However, another study demonstrated that patients treating with Reumalex® did not experience improved pain as measured by the revised Arthritis Impact Measurement Scale, although there was a significant change in modified Ritchie articular index in the RA patients [68].
  1. 2.

    Angelica Sinensis (AS)

     

AS, also known as “female ginseng” in China, was first recorded in the Shen Nong Ben Cao Jing (神農本草經) during the Eastern Han Dynasty (25–220 AD). Its medicinal use included enriching blood, invigorating circulation and treating menstrual disorders [69]. AS can be used alone or in combination with other herbs as prescriptions for the treatment of inflammatory related disease [70] and bone injuries [71]. The main groups of compounds found in AS includes coumarins, phytosterols, polysaccharides, ferulate, and flavonoids.

Previous studies demonstrated an anti-inflammatory effect of AS extract [7274]. The aqueous extract of AS significantly inhibited the production of TNF-α and IL-1β in ultra high molecular weight polyethylene (UHMWPE) particles induced RAW264.7 cell, suggesting that AS could inhibit bone resorption by attenuating proinflammatory cytokines [73]. Ethyl acetate (EtOAc) soluble extract of AS inhibited the secretion of nitric oxide and PGE2 in LPS/IFN-γ stimulated BALB/c mice peritoneal macrophages via the suppression of the NF-κB pathway [72]. A similar study also demonstrated that AS extract not only inhibited the secretion of nitric oxide and PGE2 [74, 75], but also inhibited production of cytokines, including TNF-α, IL-6, and macrophage inflammatory protein-2 (MIP-2), in LPS/IFN-γ-stimulated RAW 264.7 cells [74]. The study revealed that ferulic acid and Z-ligustilide contributed to the anti-inflammatory effect in AS EtOAc fraction by modulating the NF-κB trans-activation activity [74]. n-Butylidenephthalide significantly decreased the secretion of TNF-α, and IL-6 in LPS-stimulated murine DC2.4 cells via the suppression of NF-κB pathway [76]. Ferulic acid is thought to be one of the most biologically active components in AS, with anti-arthritic effects [77, 78]. Ferulic acid inhibited the expression of IL-1β, TNF-α, MMP-1 and MMP-13 in hydrogen peroxide-induced chondrocytes [70]. Others including the volatile oil and the polysaccharide of AS have been found to exert anti-angiogenic effects and immunomodulatory activity by regulating the expression of Th1 and Th2 related cytokines, respectively [79, 80].

In vivo, the aqueous extract of AS inhibited UHMWPE particle-induced bone resorption in C57BL/J6 mice. The production of TNF-α and IL-1β, the bone resorption area, the inflammatory infiltrate, as well as TRAP (+) osteoclasts were decreased [73]. In addition, the EtOAc extract of AS increased the survival rate of the LPS challenged BALB/c mice by inhibiting serum TNF-α, MIP-2 and IL-12p40 levels [74]. A prescription containing AS has been used clinically to treat musculoskeletal pain and arthritis [81]. Using the murine air pouch model of inflammation, the extract was shown to reduce IL-6 and TNF-α mRNA levels as well as the PGE2 concentration in the pouch fluid in monosodium urate (MSU) crystal- stimulated BALB/c mice [81]. Moreover, it reduced the migration of neutrophils into the pouch membrane of the mice [81].
  1. 3.

    Licorice (LR)

     

LR, the dried roots of Glycyrrhiza species, has been used since the Former Han era (the 2nd-3rd century B.C.) in ancient China [82]. The herb is also native to Southern Europe and parts of Asia [83]. LR has been clinically used for treating patients with tuberculosis [84], mouth and peptic ulcers [85, 86], sore throat, cough, arthritis and allergies [87].

LR has been documented to possess strong anti-inflammatory activity [88, 89]. The acetone extract of LR significantly inhibited LPS-stimulated nitric oxide, IL-1β, IL-6, and PGE2 production in J774A.1 murine macrophages [88, 89]. The effect had been shown to be mainly due to the presence of bioactive compounds glabridin and isoliquiritigenin [88, 89]. A similar study demonstrated that the EtOH extract of LR can inhibit IL-6, TNF-α, nitric oxide and PGE2 production in LPS-stimulated RAW264.7 cells [90]. Using the same bioassay system, glycyrrhizin was shown to be responsible for the inhibitory effect on nitric oxide production [91, 92], whereas liquiritigenin was found to suppress the production of TNF-α, IL-1β and IL-6 [92, 93]. Another important compound from LR, glycyrol, was found to inhibit the production of nitric oxide, PGE2, IL-1β and IL-6 [92]. The water extracts of both roasted and raw LR did not show any anti-inflammatory effects [90]. However, after further purification using column chromatography, its subfractions showed anti-inflammatory effects using the Lipoxygenase Inhibitor Screening Assay (LISA) Kit [94]. Licochalcone C isolated from LR was found to be able to attenuate the LPS-IFN-γ-induced inflammatory response by significantly decreasing the expression and activity of iNOS through the NF-κB pathway [95].

In vivo, the aqueous extract of LR showed anti-inflammatory activity against carrageenan-induced paw edema in male albino rats [96]. Moreover, the EtOH extract of LR increased the survival rate of LPS treated mice via inhibiting the production of proinflammatory cytokines IL-6 and TNF-α, and increasing the production of the anti-inflammatory cytokine IL-10 in the plasma of the mice [90]. Using a mouse collagen-induced arthritis (CIA) model, LR EtOH extract was found to reduce arthritis score and paw swelling by reducing the expression of MMP-3 in inflammatory articular cartilage and inhibiting the production of IL-1β and TNF-α in CIA mice [97]. Kim et al. also demonstrated that the EtOH extract of roasted LR showed more potent suppression of mouse ear edema induced by TPA (12-O-tetradecanoylphorbol-13-acetate) than the raw LR [97]. The effect is mainly due to the presence of glycyrrhizin and the higher amount of licochalcone A in roasted LR extract, and both of them possessed anti-arthritic effect [97]. Glycyrrhizin had anti-arthritic and anti-inflammatory effect on formaldehyde induced rat-paw edema in adrenalectomized rats [98]. Another study demonstrated that a combination therapy of glycyrrhizin with triptolide significantly reduced the arthritic index of CIA rats and the level of TNF-α in the serum of rats [99]. In addition, liquiritigenin treatment inhibited the formation of paw oedema of rats induced by carrageenan [93].
  1. 4.

    Tripterygium Wilfordii (TW)

     

TW is a vine-like plant which is found in southern part of China [100]. As a member of the Celastraceae family, TW has been commonly used to treat many autoimmune and inflammatory diseases. They include RA, systemic lupus erythematosus (SLE), ankylosing spondylitis, psoriasis, and idiopathic IgA nephropathy [101, 102]. It has even been used in clinical practice to treat arthritis [101]. TW consists of more than 70 constituents, including diterpenes, triterpenes, glycosides, and alkaloids [103]. Triptolide (TP), a diterpenoid triepoxide which is known to be a very toxic ingredient, is believed to be the major bioactive compounds contributing to the therapeutic effects on RA. It has been used as a lead molecule in the pharmaceutical industry in new drug development.

TW is believed to exert modulatory effects on immune cells. TW was found to be anti-inflammatory by its ability to inhibit nitric oxide production via NF-κB pathways in LPS-treated macrophages [104]. On the other hand, TW can be immunostimulatory, as it induces nitric oxide production in previously untreated macrophages [104]. In addition, TW extracts exert immunomodulatory effects by inhibiting T cell proliferation induced by different antigens and mitogens though the suppression of IL-2 production [105]. High levels of PGE2 are usually observed in synovial cells from arthritis patients and it is believed to play a role in pathogenesis of RA [106]. In different studies, TW is also found to suppress PGE2 production in stimulated synovial cells or fibroblast cells. The mechanisms are mainly through COX-2 inhibition via NF-κB pathways [107, 108]. One of the adverse outcomes of RA is the impairment of joint function. This can be due to destruction of ECM components, which is affected by MMPs [109]. TW inhibited the expression of MMP-3 and MMP-13 in cytokine stimulated chondrocytes and fibroblast, and the inhibition was due to the impaired binding activities of transcription factors including AP-1 and NF-κB [110].

Besides using in vitro models, the effects of TW on arthritis have been investigated in different in vivo models. One of commonly used models is arthritis induced by adjuvants in rats. In some studies, TW was found to inhibit adjuvant induced-paw oedema, joint swelling and structural damage in rats [111, 112]. Carrageenan is another inducer used to trigger inflammatory responses in rats. Previous studies demonstrated that TW inhibited the production of PGE2, TNF-α and nitrite while it suppressed the mRNA level of COX-2 in carrageenan- induced inflammation in rats [113]. Using a type II collagen-induced arthritis model, TW extract reduced the incidence and delayed the onset of arthritis in mice [114]. It also decreased the number of the arthritic joints, arthritic severity scores, and anticollagen antibody titers, resulting in the prevention of CIA development in mice [114]. Due to its wide usage and satisfactory outcomes from preliminary research, TW extract has been tested in clinical trials. In a phase I study, TW was found to be safe even in high dose and it also exerted beneficial effects in arthritis patients [115]. Similar results were obtained in another double-blind and placebo-controlled study [116].

TP is the most studied and is also believed to be the main bioactive constituent in TW for treating RA, nephritis, and pulmonary diseases [103]. It was found to be anti-inflammatory from a number of studies. TP can inhibit the production and gene expression of various cytokines and chemokines including IL-1β, IL-6, TNF-α, IFN-γ, MCP-1, MIP-1α, MIP-1β when peripheral blood mononuclear cells were stimulated by LPS or superantigen (toxic shock staphylococcal toxin-1) [117]. Moreover, TP could exert immunosuppressive functions by inhibiting T-cell proliferation induced by staphylococcal exotoxins (SE) [117]. In addition, TP was found to suppress nitric oxide production and the corresponding iNOS protein and mRNA in LPS-challenged primary murine peritoneal macrophages [102]. Furthermore, TP could reduce PGE2 production via COX-2 gene suppression and also inhibit IL-1α, IL-1β, TNF-α, and IL-6 gene expressions in macrophages [118].

TP can also exert immunomodulatory effects on other immune cells such as dendritic cells (DC), which play a crucial role in the linkage between innate immunity and adaptive immunity. One study demonstrated that TP reduced the chemoattraction of neutrophils and T cells by DC, in response to LPS, via suppression of chemokines including MIP-1α, MIP-1β, MCP-1, RANTES, TARC, and IP-10 [119]. The effects were mainly due to the inhibition of NF-κB activation and Stat3 phosphorylation and the enhancement of SOCS1 expression [119]. Th17 cells, a third independent T-helper cell subset plays an important role in autoimmune diseases including rheumatoid arthritis. In a recent study, TP significantly inhibited the generation of Th17 cells from murine splenocytes and purified CD4+ T cells by suppressing the transcription of IL-17 mRNA and IL-6-induced phosphorylation of STAT3, which is a key signaling molecule involved in the development of Th17 cells [120]. IL-18 is involved in pathogenesis of RA as well [121]. Previous studies demonstrated that TP decreased IL-18 and IL-18R protein and mRNA levels in phorbol 12-myristate 13-acetate (PMA) induced synovial fibroblasts from RA patients, by influencing the NF-κB pathway [122]. Apart from its immunoregulatory effect, TP also exerts beneficial effects on RA by controlling the production of MMPs [109]. TP suppressed the production and mRNA levels of pro-MMP-1 and -3 on human synovial fibroblasts induced by IL-1α [118]. Another study showed similar results in which TP inhibited cytokine induced MMP-3, MMP-13 and aggrecanase-1 gene expression on chondrocytes and synovial fibroblasts [123].

The beneficial effects of TP on RA were investigated in in vivo models. It was found that TP decreased the arthritic score and incidence and delayed the onset of the injury in type II collagen induced rats and mice [124126]. One of the underlying mechanisms may be related to its immunomodulatory effect. Peyer’s patches are part of the enteric mucosal immune system and are regarded as possible sites for inducing immune tolerance, which correlates with arthritis severity [127]. TP reduced CD4+ and CD8+ cells in Peyer’s patches, suggesting that there is a potential regulatory activity of TP on Peyer’s patches, thereby induce immunosuppressive responses [124, 125]. Along these lines, TGF-β is an anti-inflammatory cytokine which can contribute to immunosuppression in arthritis [128]. Studies showed that TP increased the production of TGF-β in both mice and rat arthritis models induced by type II collagen [125, 129]. TP reduced gene expressions of pro-inflammatory cytokines including IL-1β, IL-6 and TNF-α and PGE2 in a type II collagen induced arthritis model [130]. Besides regulating the immune response, TP reduced chemokine production, including MMP-3 and 13 levels, while increasing TIMP-1 and 2, which are tissue inhibitors of MMPs [130].
  1. 5.

    Centella Asiatica (CA)

     

CA, is a clonal and perennial creeper belonging to the family Umbellifere (Apiceae). It can be found in tropical and subtropical countries including India, Pakistan, Sri Lanka, Madagascar, South Africa, South pacific and Eastern Europe [131]. It has been greatly used in India and China as medicine for thousands of years [132, 133]. It is widely utilized as a blood purifier, for treating high blood pressure, memory enhancement, mental fatigue anxiety, and for promoting longevity [134].

The anti-inflammatory effects of CA were studied using acetic acid induced ulcer model [135]. Inflammatory responses, including the increased production of nitric, oxide were studied by luminal application of acetic acid to rats. CA was found to suppress nitric oxide production by reducing the activity of iNOS. The result was similar to the iNOS inhibitor N-[3-(aminomethyl)benzyl]acetamidine (1400 W) [135]. Moreover, CA extracts exerted protective effects on carrageenan and PGE2 induced rat oedema models [136, 137]. CA extract led to a reduction in the volume of the oedema, probably due to its anti-inflammatory effects [136, 137].

In addition to inflammation, reactive oxygen species including hydrogen peroxide also play an important role in the pathogenesis of RA by causing tissue damage to the patients. Hydrogen peroxide administration can lead to lipid peroxidation which results in increased malonaldehyde (MDA) level in blood. With the treatment of CA, the MDA level was reduced [138], suggesting that CA can protect against lipid peroxidation in RA.

Madecassoside (MA) is one of the most abundant triterpenoid constituents in CA and is believed to be the major bioactive compounds in the treatment of RA [139]. The anti-inflammatory effects of MA were studied using LPS-induced macrophages [140]. The production of nitric oxide, PGE2, TNF-α, IL-1β, and IL-6 were increased upon LPS treatment. With the use of MA, these increases were significantly reduced. The underlying mechanism of action may be due to the inhibition of protein and mRNA levels of iNOS and COX-2 as well as NF-κB and DNA binding [140].

The protective effects of MA on arthritis were studied using type II collagen induced arthritis in mice [141, 142]. MA was demonstrated to exert beneficial effects by reducing paw oedema, arthritic score and pathological damage to joint tissue. The effect was found to be related to its anti-inflammatory functions. Administration of MA suppressed the infiltration of inflammatory cells and proliferations of T-cells. PGE2, TNF-α and IL-6 levels were suppressed while anti-inflammatory cytokine levels (e.g. IL-10) were increased by MA [141, 142].
  1. 6.

    Urtica Dioica (UD)

     

UD is a plant belonging to the plant family Urticaceae. It has been widely used for treating benign prostatic hyperplasia in Europe [143]. Moreover, it has been utilized for treating RA, osteoarthritis and increased diuresis [144]. It is believed that its biological effects are due to phytochemicals including lignans, flavonoids, polysaccharides, lectins and steroids [145].

The anti-inflammatory effects of UD extract were studied using different LPS challenge models [146, 147]. UD was found to inhibit the production of cytokines including TNF-α, IL-1β [146] and nitric oxide [147] in LPS-stimulated human whole blood and primary mouse peritoneal macrophages, respectively. Transcription factors of the NF-κB family plays an essential role for inducing expansion of many inflammatory genes, including TNF-α [148]. UD was found to inhibit NF-κB-DNA binding, NF-κB reported gene expression and IκB degradation in TNF-α stimulated human epithelial cells. This may partly explains the anti-inflammatory functions of UD [149].

Dendritic cells play an important role in T-cell activation. Immature dendritic cells have a high affinity for antigens. After differentiation, the mature dendritic cells present the processed antigens to T-cells [150]. The activation of T-cells then leads to enhanced local inflammation, recruitment of granulocytes or macrophages, which in turn can cause degenerative changes of joints in RA patients [151]. In a previous study, UD extracts were found to inhibit the maturation of dendritic cells by reducing the expression of CD83+ and CD86+ cells, which are surface markers of mature dendritic cells. Moreover, it increased the expression of CCR-5+ and CD-36+ cells, leading to reduced induction of primary T cell responses [151]. In addition, MMPs play an important role in ECM degradation in joints [109]. Studies demonstrated that UD extract suppressed the proteins levels of MMP-1, -3 and -9 induced by IL-1β, suggesting that UD can be used as an IL-1β inhibitor for treating RA [152].

Conclusions

The unsatisfactory outcome of current drugs for treating rheumatoid arthritis has led to the consideration of alternative medicine. Modern biological immunomodulators, while showing efficacy in the treatment of RA [153156], may carry as yet unknown side effects. Botanical drugs from traditional Chinese medicine have been used to treat rheumatoid arthritis since ancient times. In recent years, advanced and sophisticated research has been done on many medicinal herbs and some have demonstrated possible efficacy. With the help of modern science and technology, the chemical constituents and underlying mechanisms are being developed. Herbs including Tripterygium wilfordii Hook F. are being investigated in clinical trials. Although generally only single herb monotherapy is mentioned in this review, the use of decoction with more than one herb is a common practice, especially in traditional Chinese medicine [157159]. The balance and interaction of all the ingredients are considered more functional than the effect of a single herb treatment. It is expected that medicinal herbs will be playing an increasingly important role in the therapeutics of rheumatoid arthritis in the coming future.

Acknowledgements

This project was supported in part by grants from Prof Francis SK Lau Research Fund and PuraPharm International awarded to Prof. A Lau.

Copyright information

© Springer Science+Business Media, LLC 2012