Potassium-inhibited processing of IL-1 beta in human monocytes.
Agents that deplete cells of K+ without grossly disrupting the plasma membrane were found to stimulate the cleavage of pro-interleukin (IL)-1 beta to mature IL-1 beta. Agents examined in this study included staphylococcal alpha-toxin and gramicidin, both of which selectively permeabilize plasma membranes for monovalent ions, the ionophores nigericin and valinomycin, and the Na+/K+ ATPase inhibitor ouabain. K+ depletion by brief hypotonic shock also triggered processing of pro-IL-1 beta. The central role of K+ depletion for inducing IL-1 beta maturation was demonstrated in cells permeabilized with alpha-toxin: processing of pro-IL-1 beta was totally blocked when cells were suspended in medium that contained high K+, but could be induced by replacing extracellular K+ with Na+, choline+ or sucrose. To test whether K+ flux might also be important in physiological situations, monocytes were stimulated with lipopolysaccharide (LPS) for 1-2 h to trigger pro-IL-1 beta synthesis, and transferred to K(+)-rich medium. This maneuver totally suppressed IL-1 beta maturation. Even after 16 h, however, removal of K+ from the medium resulted in rapid processing and export of IL-1 beta. Ongoing export of mature IL-1 beta from cells stimulated with LPS for 2-6 h could also be arrested by transfer to K(+)-rich medium. Moreover, a combination of two K+ channel blockers inhibited processing of IL-1 beta in LPS-stimulated monocytes. We hypothesize that K+ movement and local K+ concentrations directly or indirectly influence the action of interleukin-1 beta-converting enzyme (ICE) and, possibly, of related intracellular proteases.
Walev
I
I
Institute of Medical Microbiology and Hygiene, University of Mainz.
Reske
K
K
Palmer
M
M
Valeva
A
A
Bhakdi
S
S
D000918:Antibody Specificity; D002463:Cell Membrane Permeability; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis* / Q000276:immunology / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000502:physiology*; D011188:Potassium / Q000378:metabolism / Q000494:pharmacology*; D026902:Potassium Channel Blockers; D011498:Protein Precursors / Q000276:immunology / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D010738:Type C Phospholipases
D007375:Interleukin-1; D008070:Lipopolysaccharides; D026902:Potassium Channel Blockers; D011498:Protein Precursors; C043830:interleukin 1 precursor; D010738:Type C Phospholipases; D011188:Potassium