Celastrol, a Chinese herbal compound, controls autoimmune inflammation by altering the balance of pathogenic and regulatory T cells in the target organ
Introduction
Chronic inflammation is a hallmark of autoimmune diseases such as rheumatoid arthritis (RA), which is characterized by inflammatory cell infiltration into the synovium, synovial hyperplasia, angiogenesis, and cartilage and bone damage [1], [2], [3]. A variety of anti-inflammatory and disease-modifying anti-rheumatic drugs are available for the treatment of RA, but their prolonged use is frequently associated with severe adverse reactions. The new category of drugs, the biologics, such as antibodies and/or decoy receptors aimed at neutralizing the pro-inflammatory cytokines such as TNF-α and IL-6 have made a major impact on the management of RA [4], [5], [6]. However, about 30–40% of patients either fail to respond or become unresponsive over time to these newer medications, and there is increased risk of infections in patients treated with biologics. In addition, biologics are expensive. Thus, newer anti-inflammatory and anti-arthritic therapeutic products are being sought. Natural products belonging to the traditional systems of medicine represent a promising resource in this regard [7]. However, for acceptance into the mainstream therapy, it is imperative that the mechanisms of action of herbal products for treatment of autoimmune diseases are better defined in the context of the contemporary immune parameters.
The T cells play an important role in the disease process in autoimmunity: the T helper 17 cells (Th17) drive pathogenic inflammation [8], [9], whereas the T regulatory cells (Treg) have been shown to protect against autoimmune diseases [10], [11]. Two major challenges remain to be further addressed in autoimmunity: first, defining the dynamics of the cellular immune responses in the target organ, particularly the relative frequency of Th17 and Treg and the resulting Th17/Treg balance; and second, identifying novel therapeutic agents that can revert an imbalance between Th17 and Treg in the target organ.
In this study, we have examined the above-stated issues using Celastrol, a bioactive component of the traditional Chinese medicine Celastrus aculeatus Merr [12], in the rat adjuvant-induced arthritis (AA) model of human RA [13]. IL-17 plays a vital role in the pathogenesis of AA [13]. However, little is known about the relative frequency of Th17 and Treg in arthritic joints in rats with AA and the influence of anti-arthritic agents on these cellular parameters. We have previously shown that Celastrol possesses anti-arthritic activity as tested in the rat AA model [14]. Furthermore, it can inhibit IL-6 production and STAT3 activation implying that it might influence Th17 differentiation [14]. Accordingly, we hypothesized that Celastrol limits the progression of arthritis in part by altering the Th17/Treg balance in the target organ to facilitate immune regulation. In addition, Celastrol may influence T cell activation and cellular migration into the joints. Our results support these propositions.
Section snippets
Induction and evaluation of adjuvant arthritis (AA)
Five week old inbred Lewis (RT.1l) rats (Harlan Laboratories, Inc.) were immunized subcutaneously (s.c.) at the base of the tail with 1 mg/rat heat-killed Mycobacterium tuberculosis H37Ra (Mtb) (Difco) in oil. The severity of arthritis was graded on the basis of erythema and swelling of the paws as described previously [13], [14].
Treatment of arthritic rats with Celastrol
Lyophilized Celastrol (EMD Millipore) was dissolved in dimethylsulfoxide (DMSO), diluted in PBS (6 μl of stock in 500 μl of PBS), and injected into arthritic rats (1
Results
We determined the phenotype of defined subsets of T cells in the target organ (the inflamed joints) of Celastrol-treated versus vehicle-treated (control) arthritic rats. The dose of Celastrol used in these experiments is effective in modulating AA as reported in our previous study [14]. The number of CD4+ T cells producing IL-17 was significantly reduced from an average of 68.8% in vehicle-treated rats to 21.8% in Celastrol-treated animals (n = 8, p < 0.05) (Fig. 1A, top right). This reduction was
Discussion
The results of our study highlighted the influence of a traditional Chinese medicinal product, Celastrol, in reducing Th17 and increasing Treg frequency in the inflamed target organ, the joints, in a model of experimental arthritis. Given the functional attributes of Th17 and Treg, this change in their balance favors an anti-inflammatory/immunomodulatory local environment in the inflamed tissue. Therefore, we suggest that a reduction in Th17/Treg ratio by Celastrol in part contributes to the
Conflict of interest statement
The authors declare that there are no conflicts of interest.
Acknowledgments
This work was supported by NIH grants R01 AT004321 and F31 AT007278. We thank Krystal Matthews for her help with the NF-κB reporter assay; Joao Pedra for advice in the testing of mature IL-1β; Qing Chen for help with testing of the composition of synovial-infiltrating cells; and Stefanie Vogel for providing the qRT-PCR facility.
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