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Human monocyte stimulus-coupled IL-1beta posttranslational processing: modulation via monovalent cations

D G Perregaux¹, C A Gabel

¹Pfizer Central Research, Groton, Connecticut 06340, USA.

The American Journal of Physiology

|December 9, 1998

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Extracellular sodium (Na+) is crucial for releasing active interleukin-1beta (IL-1beta) from monocytes after ATP stimulation. This process requires Na+ for a step before caspase-1 activation.

Area of Science:

Immunology
Cell Biology
Biochemistry

Background:

Human monocytes produce prointerleukin-1beta (pro-IL-1beta) upon lipopolysaccharide activation.
Release of mature, biologically active 17-kDa IL-1beta requires a secondary stimulus, such as ATP.
The precise ionic requirements for this ATP-induced release are not fully understood.

Purpose of the Study:

To investigate the cation requirements for ATP-induced release of mature IL-1beta from activated human monocytes.
To elucidate the role of extracellular ions in the posttranslational processing and externalization of IL-1beta.

Main Methods:

Lipopolysaccharide-activated human monocytes were stimulated with ATP in media with varying extracellular cation compositions (e.g., Na+, K+, Li+, Cl- salts, sucrose).
IL-1beta processing and release were assessed by measuring the production of 17-kDa IL-1beta.

Related Experiment Videos

The effects of ion depletion and replacement on ATP signaling pathways were evaluated.

Main Results:

Extracellular sodium (Na+) was essential for the production of 17-kDa IL-1beta; Na+-deficient media abolished processing.
Restoration of Na+ partially rescued IL-1beta production, but was inhibited by physiological concentrations of extracellular potassium (K+) or lithium (Li+).
The requirement for Na+ is downstream of ATP receptor activation and independent of caspase-1 inhibition.

Conclusions:

Extracellular Na+ is indispensable for a specific step in stimulus-coupled IL-1beta processing, occurring after initial stimulation but before caspase-1 activation.
Potassium efflux may be a necessary component of the ATP-induced IL-1beta release mechanism.
Understanding these ionic requirements provides insight into the regulation of inflammatory cytokine release.