title: B- to plasma-cell terminal differentiation entails oxidative stress and profound reshaping of the antioxidant responses.
abstract: Limited amounts of reactive oxygen species are necessary for cell survival and signaling, but their excess causes oxidative stress. H(2)O(2) and other reactive oxygen species are formed as byproducts of several metabolic pathways, possibly including oxidative protein folding in the endoplasmic reticulum. B- to plasma-cell differentiation is characterized by a massive expansion of the endoplasmic reticulum, finalized to sustain abundant immunoglobulin (Ig) synthesis and secretion. The increased production of disulfide-rich Ig might cause oxidative stress that could serve signaling roles in the differentiation and lifespan control of antibody-secreting cells. Here we show that terminal B-cell differentiation entails redox stress, NF-E2-related factor-2 (Nrf2) activation, and reshaping of the antioxidant responses. However, plasma-cell differentiation was not dramatically impaired in peroxiredoxin (Prx)1-, 2-, 3-, and 4-, glutathione peroxidase 1-, and Nrf2-knockout splenocytes, suggesting redundancy and robustness in antioxidant systems. Endoplasmic reticulum (ER)-resident Prx4 increases dramatically during differentiation. In its absence, IgM secretion was not significantly affected, but more high-molecular-weight covalent complexes accumulated intracellularly. Our results suggest that the early intracellular production of H(2)O(2) facilitates B-cell proliferation and reveal a role for the Nrf2 pathway in the differentiation and function of IgM-secreting cells.
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milano, Italy.
authors.forename: Milena
authors.initials: M
authors.lastname: Bertolotti
authors.forename: Sun Hee
authors.initials: SH
authors.lastname: Yim
authors.forename: Jose M
authors.initials: JM
authors.lastname: Garcia-Manteiga
authors.forename: Silvia
authors.initials: S
authors.lastname: Masciarelli
authors.forename: Yoo-Jin
authors.initials: YJ
authors.lastname: Kim
authors.forename: Min-Hee
authors.initials: MH
authors.lastname: Kang
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Iuchi
authors.forename: Junichi
authors.initials: J
authors.lastname: Fujii
authors.forename: Roberta
authors.initials: R
authors.lastname: Vené
authors.forename: Anna
authors.initials: A
authors.lastname: Rubartelli
authors.forename: Sue Goo
authors.initials: SG
authors.lastname: Rhee
authors.forename: Roberto
authors.initials: R
authors.lastname: Sitia
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D001402:B-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum; D007075:Immunoglobulin M / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000172:deficiency / Q000276:immunology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010950:Plasma Cells / Q000166:cytology* / Q000187:drug effects / Q000276:immunology; D017382:Reactive Oxygen Species / Q000276:immunology; D015398:Signal Transduction
chemical_list: D000975:Antioxidants; D007075:Immunoglobulin M; D008070:Lipopolysaccharides; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D017382:Reactive Oxygen Species