HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

A cyclooxygenase-2/prostaglandin E2 pathway augments activation-induced cytosine deaminase expression within replicating human B cells.

Abstract
Within inflammatory environments, B cells encountering foreign or self-Ag can develop tertiary lymphoid tissue expressing activation-induced cytosine deaminase (AID). Recently, this DNA-modifying enzyme was detected in nonlymphoid cells within several inflamed tissues and strongly implicated in malignant transformation. This study examines whether a cyclooxygenase 2 (COX-2) pathway, often linked to inflammation, influences AID expression in activated B lymphocytes. In this paper, we report that dividing human B cells responding to surrogate C3d-coated Ag, IL-4, and BAFF express AID, as well as COX-2. A progressive increase in AID with each division was paralleled by a division-related increase in a COX-2-linked enzyme, microsomal PGE(2) synthase-1, and the PGE(2)R, EP2. Cells with the greatest expression of AID expressed the highest levels of EP2. Although COX-2 inhibitors diminished both AID expression and IgG class switching, exogenous PGE(2) and butaprost, a selective EP2 agonist, augmented AID mRNA/protein and increased the numbers of IgG(+) progeny. Despite the latter, the proportion of IgG(+) cells within viable progeny generally declined with PGE(2) supplementation. This was not due to PGE(2)-promoted differentiation to plasma cells or to greater downstream switching. Rather, because phosphorylated ataxia telangiectasia mutated levels were increased in progeny of PGE(2)-supplemented cultures, it appears more likely that PGE(2) facilitates AID-dependent DNA double-strand breaks that block B cell cycle progression or promote activation-induced cell death, or both. Taken together, the results suggest that a PGE(2) feed-forward mechanism for augmenting COX-2 pathway proteins promotes progressively increased levels of AID mRNA, protein, and function.
AuthorsHyunjoo Lee, Joshua S Trott, Shabirul Haque, Steven McCormick, Nicholas Chiorazzi, Patricia K A Mongini
JournalJournal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 185 Issue 9 Pg. 5300-14 (Nov 01 2010) ISSN: 1550-6606 [Electronic] United States
PMID20921530 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • RNA, Messenger
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • AICDA (activation-induced cytidine deaminase)
  • Cytidine Deaminase
  • Dinoprostone
Topics
  • B-Lymphocytes (immunology, metabolism)
  • Cyclooxygenase 2 (immunology, metabolism)
  • Cytidine Deaminase (biosynthesis)
  • Dinoprostone (immunology, metabolism)
  • Humans
  • Immunoblotting
  • Lymphocyte Activation (immunology)
  • RNA, Messenger (analysis)
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction (immunology)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: