Vitamin A potentiates CpG-mediated memory B-cell proliferation and differentiation: involvement of early activation of p38MAPK.
Foreign CpG-DNA from viruses and bacteria can activate memory B cells through binding to toll-like receptor 9, and this pathway has been hypothesized to be involved in the continuous activation of memory B cells ensuring life-long humoral immunity. In this study, we demonstrate that retinoic acid (RA) is a potent coactivator of this pathway in human B cells. RA enhanced the CpG-mediated proliferation of CD27(+) memory B cells, and the proliferative response was accompanied by increased immunoglobulin (Ig) secretion indicative of plasma-cell formation. The RA-induced proliferation was preceded by enhanced expression of cyclin D3, and both the expression of cyclin D3 and the induced Ig secretion were found to be dependent on IL-10. Of importance, RA increased the CpG-induced phosphorylation of ERK1/2, p38MAPK, and IkappaB as early as 30 minutes after stimulation. By using specific inhibitors, all the RA-mediated events, including proliferation, cyclin D3 expression, IL-10 secretion, and Ig secretion, were shown to be dependent on p38MAPK. Hence, we propose that RA can strengthen humoral immunity by promoting CpG-mediated stimulation of CD27(+) B cells via activation of p38MAPK resulting in increased proliferation and differentiation to Ig-secreting plasma cells.
Ertesvag
Aase
A
Department of Biochemistry, Institute of Basic Medical Sciences, University of Oslo, Blindern, N-0317 Oslo, Norway.
Aasheim
Hans-Christian
HC
Naderi
Soheil
S
Blomhoff
Heidi Kiil
HK
D000276:Adjuvants, Immunologic / Q000819:agonists / Q000494:pharmacology*; D000917:Antibody Formation / Q000187:drug effects / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects* / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D056743:Cyclin D3; D016213:Cyclins / Q000276:immunology; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D020672:I-kappa B Proteins / Q000276:immunology; D007156:Immunologic Memory / Q000187:drug effects* / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology; D019950:Mitogen-Activated Protein Kinase 1 / Q000276:immunology; D048052:Mitogen-Activated Protein Kinase 3 / Q000276:immunology; D009838:Oligodeoxyribonucleotides / Q000819:agonists / Q000494:pharmacology*; D010950:Plasma Cells / Q000166:cytology / Q000276:immunology*; D013997:Time Factors; D014801:Vitamin A / Q000819:agonists / Q000494:pharmacology*; D014815:Vitamins / Q000819:agonists / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology
D000276:Adjuvants, Immunologic; C534696:CCND3 protein, human; C408982:CPG-oligonucleotide; D056743:Cyclin D3; D016213:Cyclins; D020672:I-kappa B Proteins; C508609:IL10 protein, human; D009838:Oligodeoxyribonucleotides; D014815:Vitamins; D014801:Vitamin A; D016753:Interleukin-10; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases