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and IL-1ß Occurs via a Similar Mechanism
Department of Cancer, Immunology and Infectious Diseases, Pfizer Central Research, Groton, CT 06340
In response to LPS, peritoneal macrophages produce IL-1, but, for
the most part, newly synthesized cytokine molecules remain cell
associated. Externalization and proteolytic processing of pro-IL-1ß
can be initiated by extracellular ATP. In this study, kinetics and
inhibitor sensitivity of the stimulus-coupled mechanism were
investigated with [35S]methionine-labeled
macrophages. Optimal ATP concentrations required to promote cytokine
post-translational processing suggest the involvement of a
P2Z type of receptor. Proteolysis of pro-IL-1ß initiates
within 7.5 min of ATP addition; 17-kDa mature IL-1ß is observed first
intracellularly and subsequently extracellularly. In contrast,
ATP-treated cells do not contain 17-kDa IL-1
. Macrophages exposed to
ATP continuously or only for a 15-min pulse release IL-1, IL-1ß,
and lactate dehydrogenase (LDH). Proteolytic maturation of IL-1ß
exceeds that of IL-1 in both formats, but pulsed cells process the
externalized cytokines more efficiently. Ethacrynic acid and DIDS
(4,4'-diisothiocyanato-stilbene-2,2'-disulfonic acid) block ATP-induced
proteolysis of pro-IL-1ß and prevent release of pro-IL-1/ß and
LDH; they do not inhibit ATP-induced K+
(86Rb+) efflux. Ethacrynic acid inhibits
release of both forms of IL-1 with a similar concentration dependence;
within the arrested cells, procytokines accumulate in a
Triton-insoluble fraction. An IL-1ß-converting enzyme inhibitor
blocks proteolysis of IL-1ß, but it does not prevent release of
pro-IL-1, pro-IL-1ß, or LDH. These results indicate that ATP
stimulates externalization of both IL-1 and IL-1ß. The ATP-induced
cytokine release mechanism is accompanied by cell death and requires
activity of an anion transport inhibitor-sensitive component, but this
pathway operates independently of cytokine proteolytic processing.
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