Mechanisms of processing and secretion of IL-1β in fish (94.30)

Abstract

Abstract IL-1β is a potent pro-inflammatory cytokine which is translated as a leaderless 33 kDa precursor protein (proIL-1β) that is processed into its 17 kDa active form by the IL-1β-converting enzyme (ICE, caspase-1). Several stimuli have been reported to activate caspase-1, including the engagement of P2X7 receptors by extracellular ATP and infection with invasive bacteria. While the recognition site for caspase-1 is well conserved in mammals, most of the non-mammalian IL-1β genes cloned so far lack this conserved site. In addition, we have previously shown that extracellular ATP fails to induce the processing and release of this cytokine in the bony fish gilthead seabream. In this study, we report that the stimulation of seabream leukocytes with flagellin or bacterial DNA leads to the processing of proIL-1β into a 20 kDa form, although it largely remains intracellular. However, the infection of leukocytes with salmonella results in the efficient and specific release of the mature form. Interestingly, the processing of IL-1β in this species is not prevented by a specific inhibitor of caspase-1 or a pan-caspase inhibitor. Whatever the case, our results suggest that the processing and release of IL-1β in early vertebrates is mediated by cell death upon bacterial infection by a caspase-1 independent mechanism, while a more sophisticated mechanism operated by activation of ATP-gated P2X7 receptors appeared later in evolution. This work was supported by the Spanish Ministry of Education and Science (grant BIO2005-05078 to V.M. and fellowship to G.L.-C.).