title: Effective treatment of rat adjuvant-induced arthritis by celastrol.
abstract: We have previously reported an increase in interleukin (IL)-1β and IL-17 levels, and a continuous activation of caspase-1 in early rheumatoid arthritis (RA) patients. These results suggest that drugs targeting IL-1β regulatory pathways, in addition to tumor necrosis factor (TNF), may constitute promising therapeutic agents in early RA. We have recently used a THP-1 macrophage-like cell line to screen 2320 compounds for those that down-regulate both IL-1β and TNF secretion. Celastrol was one of the most promising therapeutic candidates identified in that study. Our main goal in the present work was to investigate whether administration of celastrol is able to attenuate inflammation in a rat model of adjuvant-induced arthritis (AIA). Moreover, since IL-1β is known to play a role in the polarization of Th17 cells, we also investigate whether administration of digoxin, a specific inhibitor of Th17 cells polarization, is able to attenuate inflammation in the same rat model. We found that celastrol administration significantly suppressed joint inflammation. The histological and immunohistochemical evaluation revealed that celastrol-treated rats had a normal joint structure with complete abrogation of the inflammatory infiltrate and cellular proliferation. In contrast, we observed that digoxin administration significantly ameliorated inflammation but only if administrated in the early phase of disease course (after 4days of disease induction), and it was not efficient at inhibiting the infiltration of immune cells within the joint and in preventing damage. Thus, our results suggest that celastrol has significant anti-inflammatory and anti-proliferative properties and can constitute a potential anti-inflammatory drug with therapeutic efficacy in the treatment of immune-mediated inflammatory diseases such as RA. Furthermore, we find that early inhibition of Th17 cells polarization ameliorates arthritis but it is not as effective as celastrol.
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal. ritacascao@gmail.com
authors.forename: R
authors.initials: R
authors.lastname: Cascão
authors.forename: B
authors.initials: B
authors.lastname: Vidal
authors.forename: H
authors.initials: H
authors.lastname: Raquel
authors.forename: A
authors.initials: A
authors.lastname: Neves-Costa
authors.forename: N
authors.initials: N
authors.lastname: Figueiredo
authors.forename: V
authors.initials: V
authors.lastname: Gupta
authors.forename: J E
authors.initials: JE
authors.lastname: Fonseca
authors.forename: L F
authors.initials: LF
authors.lastname: Moita
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000188:drug therapy*; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D004077:Digoxin / Q000008:administration & dosage* / Q000009:adverse effects; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors; D007596:Joints / Q000187:drug effects* / Q000276:immunology; D053978:Pentacyclic Triterpenes; D051381:Rats; D017208:Rats, Wistar; D058504:Th17 Cells / Q000187:drug effects* / Q000276:immunology; D014315:Triterpenes / Q000008:administration & dosage* / Q000494:pharmacology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D053583:Interleukin-1beta; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; D004077:Digoxin; C050414:celastrol