Abstract

In previous studies we identified the fungal macrocyclic lactone (S)-Curvularin (SC) as an anti-inflammatory agent using a screening system detecting inhibitors of the JAK/STAT-pathway. The objective of the present study was to investigate whether SC is able to decrease pro-inflammatory gene expression in an in-vivo model of a chronic inflammatory disease. Therefore, the effects of SC and dexamethasone were compared in the model of collagen induced arthritis (CIA) in mice. Total genomic microarray analyses were performed to identify SC target genes. Also in human C28/I2 chondrocytes the effect of SC on pro-inflammatory gene expression was tested on RNA- and protein-level. In the CIA model SC markedly reduced the expression of a number of pro-inflammatory cytokines and chemokines involved in the pathogenesis of CIA as well as human RA. In almost all cases the effects of SC were comparable to those of dexamethasone. In microarray analyses we identified additional new therapeutic targets of SC. Some of them, such as S100A8, myeloperoxidase or cathelicidin, an antimicrobial peptide, are known to be implicated in pathophysiological processes in RA. Similar anti-inflammatory effects of SC were also observed in human C28/I2 chondrocyte cells, which are resistant to GC treatment. These data indicate that SC and GC effects are mediated via independent signal transduction pathways. In summary, we demonstrate that SC is a new effective anti-inflammatory compound, which may serve as a lead compound for the development of new drugs for the therapy of chronic inflammatory diseases.