| First Author | Kim EY | Year | 2014 |
| Journal | FASEB J | Volume | 28 |
| Issue | 10 | Pages | 4347-58 |
| PubMed ID | 25002116 | Mgi Jnum | J:217572 |
| Mgi Id | MGI:5614548 | Doi | 10.1096/fj.14-251611 |
| Citation | Kim EY, et al. (2014) Role of sphingosine kinase 1 and sphingosine-1-phosphate in CD40 signaling and IgE class switching. FASEB J 28(10):4347-58 |
| abstractText | The tumor necrosis factor (TNF) receptor family member CD40 plays an essential role in the activation of antigen-presenting cells, B cell maturation, and immunoglobulin (Ig) class switching critical for adaptive immunity. Although the bioactive sphingolipid metabolite sphingosine-1-phosphate (S1P) and the kinase that produces it, sphingosine kinase 1 (SphK1), have long been implicated in the actions of TNF mediated by engagement of TNFR1, nothing is yet known of their role in CD40-mediated events. We have now found that ligation of CD40 activates and translocates SphK1 to the plasma membrane, leading to generation of S1P. SphK1 inhibition in human tonsil B cells, as well as inhibition or deletion of SphK1 in mouse splenic B cells, significantly reduced CD40-mediated Ig class switching and plasma cell differentiation ex vivo. Optimal activation of downstream CD40 signaling pathways, including NF-kappaB, p38, and JNK, also required SphK1. In mice treated with a SphK1 inhibitor or in SphK1(-/-) mice, isotype switching to antigen-specific IgE was decreased in vivo by 70 and 55%, respectively. Our results indicate that SphK1 is important for CD40-mediated B cell activation and regulation of humoral responses and suggest that targeting SphK1 might be a useful therapeutic approach to control antigen-specific IgE production. |
