Abstract
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.
Highlights
Interleukin-1 (IL-1)1 and tumor necrosis factor (TNF) belong to a group of pro-inflammatory cytokines with overlapping biological activities, which might be brought about by common signaling mechanisms [1,2,3]
We have previously described an IL-1RI-positive subclone of EL4 cells, EL4D6/76, This paper is available on line at http://www.jbc.org
After binding of IL-1 only EL4 5D3 but not EL4D6/76 reacted with increased IL-2 production in presence of the tumor promoter PMA [39]. To investigate whether this defect of EL4D6/76 was restricted to IL-1 cells were stimulated with TNF and/or PMA
Summary
Interleukin-1 (IL-1)1 and tumor necrosis factor (TNF) belong to a group of pro-inflammatory cytokines with overlapping biological activities, which might be brought about by common signaling mechanisms [1,2,3]. Ceramide produced by A-SMase provides an important signal for further downstream events like NFB activation or IL-2 production. In contrast to IL-1, co-stimulation with TNF and PMA led to increased IL-2 production in both cell lines (Fig. 1A), indicating the specificity of the functional defect in EL4D6/76 cells.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
