A differential role for ceramide kinase in antigen/FcɛRI-mediated mast cell activation and function
Article first published online: 24 JAN 2011
© 2011 Blackwell Publishing Ltd
Clinical & Experimental Allergy
Volume 41, Issue 3, pages 389–398, March 2011
How to Cite
Hewson, C. A., Watson, J. R., Liu, W. L. and Fidock, M. D. (2011), A differential role for ceramide kinase in antigen/FcɛRI-mediated mast cell activation and function. Clinical & Experimental Allergy, 41: 389–398. doi: 10.1111/j.1365-2222.2010.03682.x
- Issue published online: 7 FEB 2011
- Article first published online: 24 JAN 2011
- Submitted 29 March 2010; revised 26 November 2010; accepted 29 November 2010.
- ceramide kinase;
- mast cell
Cite this as: C. A. Hewson, J. R. Watson, W. L. Liu and M. D. Fidock, Clinical & Experimental Allergy, 2011 (41) 389–398.
Background Mast cells are specialized secretory cells releasing multiple inflammatory mediators when activated. Activation requires antigen/IgE cross-linking of FcɛRI receptors, initiating a complex intracellular signalling cascade. Ceramide kinase (CERK) is a novel lipid kinase implicated in several inflammatory cellular signalling processes.
Objective We sought to investigate a role for CERK in FCɛRI/IgE-mediated mast-cell activation.
Methods The rat and human mast cell-lines RBL-2H3 and LAD-2, respectively, were stimulated via FcɛRI or with the active product of CERK [ceramide-1-phosphate (C-1P)]. Multiple end-points were measured by enzyme-linked immunosorbent assay; histamine (pre-formed early-phase mediator), prostaglandin D2 (PGD2– rapidly metabolized early-phase mediator) and interleukin (IL) -13 (de novo transcribed late-phase mediator).
Results We demonstrated that C-1P alone induced release of histamine and PGD2 and was additive to antigen-mediated activation. C-1P did not stimulate IL-13 by a statistically significant amount. Using a specific inhibitor of CERK, antigen-mediated release of histamine and PGD2 was significantly inhibited. Finally, we identified that, for histamine, CERK was downstream of spleen tyrosine kinase, phosphoinositol-3 kinases and phospholipase C, but upstream of c-jun N-terminal kinase (JNK); while for PGD2 CERK was positioned upstream of JNK, mitogen-activated protein kinase kinase and cyclooxygense.
Conclusions and Clinical Relevance We have identified a differential role for CERK in mast-cell activation and begun to elucidate its position in the mast cell-signalling cascade, thereby suggesting a model by which CERK may be mediating its effects. This type of study is essential for complete understanding of activation pathways that may eventually be used to identify new targets for drug discovery in inflammatory diseases.