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FASEB J. 2014 Oct;28(10):4347-58. doi: 10.1096/fj.14-251611. Epub 2014 Jul 1.

Role of sphingosine kinase 1 and sphingosine-1-phosphate in CD40 signaling and IgE class switching.

Author information

1
Department of Biochemistry and Molecular Biology.
2
Department of Microbiology and Immunology, and.
3
Department of Medicinal Chemistry, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
4
Department of Biochemistry and Molecular Biology, sspiegel@vcu.edu.

Abstract

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-κB, 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.

KEYWORDS:

B cells; NF-κB; inflammation; sphingolipids

PMID:
25002116
PMCID:
PMC4202100
DOI:
10.1096/fj.14-251611
[Indexed for MEDLINE]
Free PMC Article

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