Prostaglandin E2 promotes B lymphocyte Ig isotype switching to IgE.
The mechanism by which PG of the E series (PGE) promote murine B lymphocyte IgE production was investigated. We previously reported that PGE, and other agents that increase intracellular cAMP, synergize with IL-4 and LPS to induce IgE and IgG1 production while inhibiting IgM and IgG3 synthesis. These data suggested that PGE may promote IL-4-induced class switching, but the mechanism by which PGE increases IgE synthesis remained obscure. We report here that 1) PGE increases (up to 14-fold) the number of splenic B cells secreting IgE, even though PGE mildly inhibits proliferation. 2) PGE acts on sorted surface IgM positive B cells, consistent with PGE acting on uncommitted B cells to promote class switching to IgE. 3) PGE synergizes with IL-4 to induce germline epsilon transcripts, demonstrating that PGE acts at the level of transcription in cells that have not yet switched to IgE. 4) In the presence of PGE, rearranged mature V(D)J epsilon mRNA transcripts can be detected earlier and at higher levels than with IL-4 and LPS alone. Taken together, these data provide strong evidence that PGE synergizes with IL-4 and LPS to direct isotype switching to the epsilon heavy chain gene in purified B lymphocytes. PGE is a potentially important in vivo immunoregulator, particularly with regard to IgE production and the genesis of allergy. In support of this hypothesis, there are numerous clinical conditions (hyper-IgE, trauma, sepsis, Hodgkin's lymphoma, arthritis) in which overproduction of PGE is coincident with elevated IgE titers.
Roper
R L
RL
Immunology and Immunotherapy Division of the Cancer Center, University of Rochester School of Medicine and Dentistry, New York.
Brown
D M
DM
Phipps
R P
RP
D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D001483:Base Sequence; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000502:physiology; D015232:Dinoprostone / Q000494:pharmacology* / Q000502:physiology; D004357:Drug Synergism; D004797:Enzyme-Linked Immunosorbent Assay; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain / Q000187:drug effects; D017578:Immunoglobulin Class Switching / Q000187:drug effects*; D007073:Immunoglobulin E / Q000096:biosynthesis*; D007143:Immunoglobulin Heavy Chains / Q000096:biosynthesis / Q000235:genetics; D007132:Immunoglobulin Isotypes / Q000276:immunology*; D007075:Immunoglobulin M / Q000096:biosynthesis; D007139:Immunoglobulin epsilon-Chains / Q000096:biosynthesis / Q000235:genetics; D015847:Interleukin-4 / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis; D011947:Receptors, Antigen, B-Cell / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects*
D007143:Immunoglobulin Heavy Chains; D007132:Immunoglobulin Isotypes; D007075:Immunoglobulin M; D007139:Immunoglobulin epsilon-Chains; D012333:RNA, Messenger; D011947:Receptors, Antigen, B-Cell; D015847:Interleukin-4; D007073:Immunoglobulin E; D000242:Cyclic AMP; D015232:Dinoprostone