title: A molecular mechanism for TNF-α-mediated downregulation of B cell responses.
abstract: B cell function with age is decreased in class switch recombination (CSR), activation-induced cytidine deaminase (AID), and stability of E47 mRNA. The latter is regulated, at least in part, by tristetraprolin (TTP), which is increased in aged B cells and also negatively regulates TNF-α. In this study, we investigated whether B cells produce TNF-α, whether this changes with age, and how this affects their function upon stimulation. Our hypothesis is that in aging there is a feedback mechanism of autocrine inflammatory cytokines (TNF-α) that lowers the expression of AID and CSR. Our results showed that unstimulated B cells from old BALB/c mice make significantly more TNF-α mRNA and protein than do B cells from young mice, but after stimulation the old make less than the young; thus, they are refractory to stimulation. The increase in TNF-α made by old B cells is primarily due to follicular, but not minor, subsets of B cells. Incubation of B cells with TNF-α before LPS stimulation decreased both young and old B cell responses. Importantly, B cell function was restored by adding anti-TNF-α Ab to cultured B cells. To address a molecular mechanism, we found that incubation of B cells with TNF-α before LPS stimulation induced TTP, a physiological regulator of mRNA stability of the transcription factor E47, which is crucial for CSR. Finally, anti-TNF-α given in vivo increased B cell function in old, but not in young, follicular B cells. These results suggest new molecular mechanisms that contribute to reduced Ab responses in aging.
authors: Department of Microbiology and Immunology, University of Miami, Miami, FL 33101, USA.
authors: Daniela
authors: D
authors: Frasca
authors: Maria
authors: M
authors: Romero
authors: Alain
authors: A
authors: Diaz
authors: Sarah
authors: S
authors: Alter-Wolf
authors: Michelle
authors: M
authors: Ratliff
authors: Ana Marie
authors: AM
authors: Landin
authors: Richard L
authors: RL
authors: Riley
authors: Bonnie B
authors: BB
authors: Blomberg
mesh_terms: D000375:Aging / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D019898:Autocrine Communication / Q000187:drug effects / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D003564:Cytidine Deaminase / Q000096:biosynthesis / Q000276:immunology; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology*; D005260:Female; D017578:Immunoglobulin Class Switching / Q000187:drug effects / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D020871:RNA Stability / Q000187:drug effects / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000276:immunology; D058127:Transcription Factor 3 / Q000276:immunology / Q000378:metabolism; D051816:Tristetraprolin / Q000096:biosynthesis / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology*; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D008070:Lipopolysaccharides; D012333:RNA, Messenger; D058127:Transcription Factor 3; D051816:Tristetraprolin; D014409:Tumor Necrosis Factor-alpha; C497553:Zfp36 protein, mouse; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase