Characterization of ATP-gated P2X(7) receptors in fish provides new insights into the mechanism of release of the leaderless cytokine interleukin-1 beta

Lopez-Castejon, Gloria, Young, Mark Thomas ORCID: https://orcid.org/0000-0002-9615-9002, Meseguer, Jose, Surprenant, Annmarie and Mulero, Victoriano 2007. Characterization of ATP-gated P2X(7) receptors in fish provides new insights into the mechanism of release of the leaderless cytokine interleukin-1 beta. Molecular Immunology 44 (6) , pp. 1286-1299. 10.1016/j.molimm.2006.05.015

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Abstract

Mammalian interleukin-1beta (IL-1beta) is produced as a biologically inactive precursor molecule, which is proteolytically cleaved to an active form by IL-1beta-converting enzyme (ICE) after the activation of P2X(7) receptor by extracellular ATP. The mechanism of IL-1beta release in non-mammalian vertebrates is largely unknown, although most of the IL-1beta gene sequences lack a conserved ICE recognition site. Here we have cloned the P2X(7) receptor from the bony fish seabream and compared agonist and antagonist profiles at this and other non-mammalian P2X(7) receptors expressed in HEK cells, as well in seabream SAF-1 cells expressing endogenous P2X(7) receptors. We used this information to further investigate the mechanisms of IL-1beta release induced by mammalian and fish P2X(7) receptors. Despite phosphatidylserine externalization and cell permeabilization in seabream leukocytes after the addition of high BzATP concentrations, IL-1beta remained unprocessed within the cell. However, activation of rat P2X(7) receptors ectopically expressed in HEK293 together with human ICE led to the specific secretion of unprocessed seabream IL-1beta. In contrast, neither seabream nor zebrafish P2X(7) receptors induced the secretion of mammalian or fish IL-1beta when expressed in HEK293, while a chimeric receptor harboring the ATP-binding domain of seabream P2X(7) and the intracellular region of its rat counterpart did so. These findings indicate that P2X(7) receptor-mediated activation of ICE and release of IL-1beta result from different downstream signaling pathways and suggest that although the mechanisms involved in IL-1beta secretion are conserved throughout evolution, distinct inflammatory signals have been selected for the secretion of this cytokine in different vertebrates.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Subjects:	Q Science > Q Science (General) Q Science > QH Natural history > QH301 Biology
Uncontrolled Keywords:	Fish; Cytokines; Comparative immunology; Phylogeny
Publisher:	National Institute of Health
ISSN:	0161-5890
Last Modified:	25 Oct 2022 09:15
URI:	https://orca.cardiff.ac.uk/id/eprint/57837

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