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Blocking the janus-activated kinase pathway reduces tumor necrosis factor alpha-induced interlukin-18 bioactivity by caspase-1 inhibition

Marotte H, Tsou PS, Fedorova T et al. - Arthritis Research and Therapy 2014,16:R102

IL-18, a member of the IL-1 family, has been shown to play an important role in immune response and is involved in the pathogenesis of RA. The study objective was to examine the role of the JAK pathway in modulating TNFa-induced-IL18 bioactivity by reducing caspase-1 function. Caspase-1 is the protease that cleaves pro-IL-18 to IL-18, thereby activating it. In testing it was noted that by blocking the JAK pathway significantly decreased caspase-1 transcription, expression and activity showing the critical nature of the JAK pathway to caspase-1 function and IL-18 activity. The blocking of JAK also reduces IL-18 bioactivity by reducing the amount of IL-18 that reaches maturation. Compared with previous results, these data showed that the JAK pathway is a new specific pathway for IL-18 regulation.

This study shows that blocking caspase-1 is a novel way to inhibit IL-18 bioactivity induced by TNF while also suggesting a new additional mechanism to explain the benefits of JAK inhibition in the treatment of RA.

Keywords: JAK, Preclinical, MOA

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Upload date: May 2014

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