Abstract
Alphaviruses are a group of arboviruses that generate chronic inflammatory rheumatisms in humans. Currently, no approved vaccines or antiviral therapies are available to prevent or treat alphavirus-induced diseases. The aim of this study was to evaluate the repositioning of the anti-cancer molecule irinotecan as a potential modulator of the antiviral and inflammatory responses of primary human synovial fibroblasts (HSF), the main stromal cells of the joint synovium. HSF were exposed to O’nyong-nyong virus (ONNV) and polyinosinic-polycytidylic acid (PIC) to mimic, respectively, acute and chronic infectious settings. The cytokine IL-1β was used as a major pro-inflammatory cytokine to stimulate HSF. Quantitative RT-PCR analysis revealed that irinotecan at 15 µM was able to amplify the antiviral response (i.e., interferon-stimulated gene expression) of HSF exposed to PIC and reduce the expression of pro-inflammatory genes (CXCL8, IL-6 and COX-2) upon IL-1β treatment. These results were associated with the regulation of the expression of several genes, including those encoding for STAT1, STAT2, p53 and NF-κB. Irinotecan did not modulate these responses in both untreated cells and cells stimulated with ONNV. This suggests that this drug could be therapeutically useful for the treatment of chronic and severe (rather than acute) arthritis due to viruses.
Highlights
Infectious diseases are a well-recognized cause of acute arthralgia and arthritis
We investigated the potential effects of CPT-11 on the pro-inflammatory response of human synovial fibroblasts (HSF) cultured in the presence of O’nyong-nyong virus (ONNV) and polycytidylic acid (PIC)
The molecular mechanisms involved in the transition for from to chronic are still unclear
Summary
Infectious diseases are a well-recognized cause of acute arthralgia and arthritis. There is currently a lack of accurate data on the incidence and prevalence of viral arthritis worldwide. Studies performed on patients affected by acute arthritis have suggested a viral origin in about 1% of cases [1]. Alphaviruses are enveloped positive-sense RNA viruses transmitted by bites of infected mosquitoes and are importantly involved in inflammatory diseases, including arthritis and encephalitis [3]. “Old World” alphaviruses, of which Chikungunya virus (CHIKV) is the most well-known, are related to rheumatic diseases in humans that can turn into a chronic form. Clinical manifestations of chronic arthralgia and arthritis after alphaviral infection range from a restriction of movements with persistence of swelling and pain located in joints to a debilitating illness [4,5]
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