Microarray-based gene expression profiling reveals the mediators and pathways involved in the anti-arthritic activity of Celastrus-derived Celastrol.
Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the joints. The prolonged use of non-steroidal anti-inflammatory drugs and other newer drugs is associated with severe adverse reactions. Therefore, there is a need for newer anti-arthritic agents. Celastrol, a bioactive component of the Chinese herb Celastrus, possesses anti-arthritic activity as tested in the adjuvant arthritis (AA) model of rheumatoid arthritis (RA). However, the mechanism of action of Celastrol has not been fully defined. We reasoned that microarray analysis of the lymphoid cells of Celastrol-treated arthritic animals might provide vital clues in this regard. We isolated total RNA of the draining lymph node cells (LNCs) of Celastrol-treated (Tc) and vehicle-treated (Tp) arthritic Lewis rats that were restimulated in vitro with the disease-related antigen, mycobacterial heat-shock protein 65 (Bhsp65), and tested it using microarray gene chips. Also tested was RNA from LNCs of control arthritic rats just before any treatment (T₀). Seventy six genes involved in various biological functions were differentially regulated by Bhsp65 in LNCs of Tp group, and 19 genes among them were shared by the Tc group. Furthermore, a group of 14 genes was unique to Tc. When Tc and Tp were compared, many of the Bhsp65-induced genes were related to the immune cells, cellular proliferation and inflammatory responses. Our results revealed 10 differentially expressed genes and 14 pathways that constituted the "Celastrol Signature". Our results would help identify novel targets for RA therapy.
Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Hua
H
Yu
Shivaprasad H
SH
Venkatesha
Kamal D
KD
Moudgil
D000818:Animals; D018501:Antirheumatic Agents / Q000008:administration & dosage*; D001169:Arthritis, Experimental / Q000188:drug therapy*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D001426:Bacterial Proteins / Q000276:immunology; D031247:Celastrus / Q000737:chemistry*; D049109:Cell Proliferation / Q000187:drug effects; D018834:Chaperonin 60 / Q000276:immunology; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D006801:Humans; D007109:Immunity / Q000187:drug effects* / Q000235:genetics; D018836:Inflammation Mediators / Q000378:metabolism; D008516:Medicine, Chinese Traditional; D020411:Oligonucleotide Array Sequence Analysis; D053978:Pentacyclic Triterpenes; D051381:Rats; D011917:Rats, Inbred Lew; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D014315:Triterpenes / Q000008:administration & dosage* / Q000009:adverse effects
D018501:Antirheumatic Agents; D001426:Bacterial Proteins; D018834:Chaperonin 60; D018836:Inflammation Mediators; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; C074119:heat-shock protein 65, Mycobacterium; C050414:celastrol