Pore-forming toxins trigger shedding of receptors for interleukin 6 and lipopolysaccharide.
Cleavage of membrane-associated proteins with the release of biologically active macromolecules is an emerging theme in biology. However, little is known about the nature and regulation of the involved proteases or about the physiological inducers of the shedding process. We here report that rapid and massive shedding of the interleukin 6 receptor (IL-6R) and the lipopolysaccharide receptor (CD14) occurs from primary and transfected cells attacked by two prototypes of pore-forming bacterial toxins, streptolysin O and Escherichia coli hemolysin. Shedding is not induced by an streptolysin O toxin mutant which retains cell binding capacity but lacks pore-forming activity. The toxin-dependent cleavage site of the IL-6R was mapped to a position close to, but distinct from, that observed after stimulation with phorbol myristate acetate. Soluble IL-6R that was shed from toxin-treated cells bound its ligand and induced an IL-6-specific signal in cells that primarily lacked the IL-6R. Transsignaling by soluble IL-6R and soluble CD14 is known to dramatically broaden the spectrum of host cells for IL-6 and lipopolysaccharide, and is thus an important mechanism underlying their systemic inflammatory effects. Our findings uncover a novel mechanism that can help to explain the long-range detrimental action of pore-forming toxins in the host organism.
Walev
I
I
Institute of Medical Microbiology and Hygiene, Johannes Gutenberg University of Mainz, Germany.
Vollmer
P
P
Palmer
M
M
Bhakdi
S
S
Rose-John
S
S
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000187:drug effects*; D001426:Bacterial Proteins; D002460:Cell Line; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D004926:Escherichia coli; D006242:Haptoglobins / Q000096:biosynthesis; D006460:Hemolysin Proteins / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D009000:Monocytes / Q000187:drug effects / Q000276:immunology*; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000187:drug effects*; D019947:Receptors, Interleukin-6; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000187:drug effects; D015398:Signal Transduction; D019311:Staurosporine / Q000494:pharmacology; D013301:Streptolysins / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D006242:Haptoglobins; D006460:Hemolysin Proteins; D018950:Lipopolysaccharide Receptors; D018123:Receptors, Interleukin; D019947:Receptors, Interleukin-6; D011994:Recombinant Proteins; D013301:Streptolysins; C025964:streptolysin O; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate