Celastrus-derived Celastrol Suppresses Autoimmune Arthritis by Modulating Antigen-induced Cellular and Humoral Effector Responses

Abstract

Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial inflammation and articular damage. Proinflammatory cytokines, antibodies, and matrix-degrading enzymes orchestrate the pathogenic events in autoimmune arthritis. Accordingly, these mediators of inflammation are the targets of several anti-arthritic drugs. However, the prolonged use of such drugs is associated with severe adverse reactions. This limitation has necessitated the search for less toxic natural plant products that possess anti-arthritic activity. Furthermore, it is imperative that the mechanism of action of such products be explored before they can be recommended for further preclinical testing. Using the rat adjuvant-induced arthritis model of human RA, we demonstrate that celastrol derived from Celastrus has potent anti-arthritic activity. This suppression of arthritis is mediated via modulation of the key proinflammatory cytokines (IL-17, IL-6, and IFN-␥) in response to the diseaserelated antigens, of the IL-6/IL-17-related transcription factor STAT3, of antibodies directed against cyclic citrullinated peptides and Bhsp65, and of the activity of matrix metalloproteinase-9 and phospho-ERK. Most of the clinical and mechanistic attributes of celastrol are similar to those of Celastrus extract. Several studies have addressed the antitumor activity of celastrol. Our study highlights the anti-arthritic activity of Celastrusderived celastrol and the underlying mechanisms. These results provide a strong rationale for further testing and validation of the use of celastrol and the natural plant extract from Celastrus as an adjunct (with conventional drugs) or alternative modality for the treatment of RA. Rheumatoid arthritis (RA)2 is a chronic debilitating autoimmune disease affecting millions of people all over the world (1-3). Both cell-mediated and humoral immune reactions participate in the pathogenesis of RA (1, 4). Several proinflammatory cytokines secreted by immune cells, including TNF-␣, IL-1␤, IL-15, IL-18, and IFN-␥, have been shown to play a role in the initiation and progression of RA (4, 5). Over the past decade, a new subset of T helper cells producing IL-17 (Th17) has become the focus of RA pathogenesis (6, 7). Induction of a Th17 response involves IL-6 and TGF-␤, as well as the transcription factors STAT3 and retinoid related orphan receptor-␥t (ROR-␥t) (8, 9). In regard to the humoral response, serum levels of anti-cyclic citrullinated protein/peptide (aCCP) antibodies correlate well with the disease severity in RA patients and serve as the specific autoantibody marker for the diagnosis of RA (10, 11). In view of the above, modulation of the proinflammatory cytokines and aCCP antibody levels is a desired goal for the management of RA.A variety of drugs are available for the treatment of RA. These include corticosteroids, nonsteroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, and biologics (1, 12). However, besides their high cost, the use of these drugs is associated with severe adverse reacti...

Celastrol Suppresses Growth and Induces Apoptosis of Human Hepatocellular Carcinoma through the Modulation of STAT3/JAK2 Signaling Cascade In Vitro and In Vivo

“…Our results also show for the first time that celastrol significantly suppressed HCC growth in nude mice, downregulated the expression of phospho-STAT3 and Ki67, and increased the levels of caspase-3 in treated group as compared with control group. Interestingly, Venkatesha and colleagues, using the rat adjuvant-induced arthritis model of human rheumatoid arthritis, recently showed that celastrol also exerts its antiarthritic activity through the suppression of STAT3 transcription factor (46). However, whether the long-term administration of celastrol may be effective for preventing the development of HCCs by targeting STAT3 signaling axis in liver cancer tumorigenesis and also if this triterpene can be used in conjunction with existing chemotherapeutic agents and targeted therapies approved by FDA for HCC treatment warrants further in-depth investigation.…”

Quinone Methides and their Prodrugs: A Subtle Equilibrium Between Cancer Promotion, Prevention, and Cure

“…For example, celastrol (5) has only been assessed against autoimmune arthritis in animal models (mice) [34]. Pristimerin (6) and cryptotrione (7) have not been investigated in any biological models to state a more precise indication than just the putative « anticancer ».…”

Celastrus and Its Bioactive Celastrol Protect against Bone Damage in Autoimmune Arthritis by Modulating Osteoimmune Cross-talk

“…(celastrus) was prepared as described previously (30,32). Briefly, roots and stem of celastrus were dried, powdered, and then extracted with 75% ethanol.…”

“…Celastrus belongs to the family Celastraceae, and celastrol represents one of the bioactive components of celastrus (30 -33). We have previously reported that both celastrus and celastrol have antiinflammatory activity and can reduce the severity of clinical arthritis in the rat adjuvant-induced arthritis (AA) model of human RA (30,32). In the present study, we investigated the influence of celastrus/celastrol on bone damage in arthritic joints of rats with AA and examined the mechanisms involved in the inhibition of inflammation-mediated bone remodeling.…”

“…(celastrus) is a traditional Chinese herbal medicine that has been used in China for centuries for the treatment of various inflammatory diseases (30,32). Celastrus belongs to the family Celastraceae, and celastrol represents one of the bioactive components of celastrus (30 -33).…”