The Anti-Inflammatory Fungal Compound (S)-Curvularin Reduces Proinflammatory Gene Expression in an In Vivo Model of Rheumatoid Arthritis

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 Janus kinase/signal transducer and activator of transcription pathway. The objective of the present study was to investigate whether SC is able to decrease proinflammatory 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. In addition, in human C28/I2 chondrocytes and MonoMac6 monocytes, the effect of SC on proinflammatory gene expression was tested at the mRNA and protein level. In the CIA model, SC markedly reduced the expression of a number of proinflammatory cytokines and chemokines involved in the pathogenesis of CIA as well as human rheumatoid arthritis (RA). In almost all cases, the effects of SC were comparable with 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 glucocorticoid treatment. These data indicate that SC and glucocorticoid effects are mediated via independent signal transduction pathways. In summary, we demonstrate that SC is a new effective anti-inflammatory compound that may serve as a lead compound for the development of new drugs for the therapy of chronic inflammatory diseases.

Endothelial Dysfunction in Tristetraprolin-deficient Mice Is Not Caused by Enhanced Tumor Necrosis Factor-α Expression

“…As shown in Fig. 5E (26). Compared with PBStreated mice we observed reduced TTP and enhanced Nox2 mRNA expression in the paws of CII-treated mice (Fig.…”

“…Induction of CIA and Measurement of mRNA Expression in Paws-CIA induction in V␤12-DBA/1 mice, RNA isolation, and mRNA expression analyses were performed as described (26). mRNA expression of TTP and Nox2 in paws of PBS-or chicken CII-treated animals was analyzed at day 33 after the first CII treatment.…”

G-protein signaling modulator-3, a gene linked to autoimmune diseases, regulates monocyte function and its deficiency protects from inflammatory arthritis

“…S1A), suggesting a potential role in immune regulatory responses. Additionally, GPSM3 mRNA was recently shown to decrease in the paw after anti-inflammatory treatment with dexamethasone in the Collagen Induced Arthritis (CIA) model (7), supporting a potential role for GPSM3 in inflammatory arthritis.…”

Regulation of Chemokine Signal Integration by Activator of G-Protein Signaling 4 (AGS4)

“…The location of the Gpsm3 gene within the class III major histocompatibility class locus suggested that AGS4/Gpsm3 is expressed primarily in the immune system, and initial observations from us and others indicated this was indeed the case (Cao et al, 2004;Kimple et al, 2004;Zhao et al, 2010;Schmidt et al, 2012;Giguère et al, 2013). We also discovered AGS4 expression in primary bone marrow-derived dendritic cells and splenocytes (Fig.…”