A molecular mechanism for TNF-α-mediated downregulation of B cell responses

Daniela Frasca, Maria Romero, Alain Diaz, Sarah Alter-Wolf, Michelle Ratliff, Ana Marie Landin, Richard L Riley, Bonnie B Blomberg

Research output: Contribution to journalArticle

42 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)279-286
Number of pages8
JournalJournal of Immunology
Volume188
Issue number1
DOIs
StatePublished - Jan 1 2012

Fingerprint

B-Lymphocytes
Down-Regulation
Tristetraprolin
Genetic Recombination
RNA Stability
B-Lymphocyte Subsets
Cultured Cells
Transcription Factors
Cytokines
Messenger RNA

ASJC Scopus subject areas

  • Immunology

Cite this

A molecular mechanism for TNF-α-mediated downregulation of B cell responses. / Frasca, Daniela; Romero, Maria; Diaz, Alain; Alter-Wolf, Sarah; Ratliff, Michelle; Landin, Ana Marie; Riley, Richard L; Blomberg, Bonnie B.

In: Journal of Immunology, Vol. 188, No. 1, 01.01.2012, p. 279-286.

Research output: Contribution to journalArticle

Frasca, Daniela ; Romero, Maria ; Diaz, Alain ; Alter-Wolf, Sarah ; Ratliff, Michelle ; Landin, Ana Marie ; Riley, Richard L ; Blomberg, Bonnie B. / A molecular mechanism for TNF-α-mediated downregulation of B cell responses. In: Journal of Immunology. 2012 ; Vol. 188, No. 1. pp. 279-286.
@article{cbbf9fdbc7844158b792fd7826116d63,
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.",
author = "Daniela Frasca and Maria Romero and Alain Diaz and Sarah Alter-Wolf and Michelle Ratliff and Landin, {Ana Marie} and Riley, {Richard L} and Blomberg, {Bonnie B}",
year = "2012",
month = "1",
day = "1",
doi = "10.4049/jimmunol.1003964",
language = "English",
volume = "188",
pages = "279--286",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "1",

}

TY - JOUR

T1 - A molecular mechanism for TNF-α-mediated downregulation of B cell responses

AU - Frasca, Daniela

AU - Romero, Maria

AU - Diaz, Alain

AU - Alter-Wolf, Sarah

AU - Ratliff, Michelle

AU - Landin, Ana Marie

AU - Riley, Richard L

AU - Blomberg, Bonnie B

PY - 2012/1/1

Y1 - 2012/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84855408862&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84855408862&partnerID=8YFLogxK

U2 - 10.4049/jimmunol.1003964

DO - 10.4049/jimmunol.1003964

M3 - Article

C2 - 22116831

AN - SCOPUS:84855408862

VL - 188

SP - 279

EP - 286

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 1

ER -