Activation of acid sphingomyelinase by interleukin-1 (IL-1) requires the IL-1 receptor accessory protein.
The cytokine interleukin-1 (IL-1) plays an important role in inflammation and regulation of immune responses, but the mechanisms of its signal transduction and cell activation processes are incompletely understood. Ceramide generated by sphingomyelinases (SMases) is known to function as an important second messenger molecule in the signaling pathway of IL-1 and tumor necrosis factor. To investigate the activation of SMases by IL-1, we used an IL-1 receptor type I (IL-1RI)-positive EL4 thymoma cell line, which is defective in IL-1R accessory protein (IL-1RAcP) expression. In this cell line (EL4D6/76), tumor necrosis factor induced ligand/receptor internalization, NFkappaB nuclear translocation, IL-2 production, and the activation of neutral (N)-SMase and acid (A)-SMase. In contrast, stimulation with IL-1 resulted only in the activation of N-SMase whereas ligand/receptor internalization, NFkappaB translocation, IL-2 production, and activation of A-SMase were not detected. Transfection of this functionally defective EL4D6/76 with IL-1RAcP cDNA restored these functions. These data suggest that A-SMase activity is strongly linked with the internalization of IL-1RI mediated by IL-1RAcP and that A-SMase and N-SMase are activated by different pathways.
Hofmeister
R
R
Department of Internal Medicine I, University of Regensburg, 93042 Regensburg, Germany.
Wiegmann
K
K
Korherr
C
C
Bernardo
K
K
Krönke
M
M
Falk
W
W
D002518:Ceramides / Q000378:metabolism; D004705:Endocytosis; D011992:Endosomes / Q000201:enzymology; D004789:Enzyme Activation; D007375:Interleukin-1 / Q000494:pharmacology*; D053577:Interleukin-1 Receptor Accessory Protein; D007376:Interleukin-2 / Q000096:biosynthesis; D016328:NF-kappa B / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D015398:Signal Transduction; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D002518:Ceramides; D007375:Interleukin-1; D053577:Interleukin-1 Receptor Accessory Protein; D007376:Interleukin-2; D016328:NF-kappa B; D011506:Proteins; D013108:Sphingomyelin Phosphodiesterase