Cross-regulation of TNF and IFN-α in autoimmune diseases

A. Karolina Palucka, Jean Philippe Blanck, Lynda Bennett, Virginia Pascual, Jacques Banchereau

Research output: Contribution to journalArticle

366 Citations (Scopus)

Abstract

Cytokines, most particularly TNF and type I IFN (IFN-αβ), have been long considered essential elements in the development of autoimmunity. Identification of TNF in the pathogenesis of rheumatoid arthritis and TNF antagonist therapy represent successes of immunology. IFN-αβ plays a major role in systemic lupus erythematosus (SLE), a prototype autoimmune disease characterized by a break of tolerance to nuclear components. Here, we show that TNF regulates IFN-α production in vitro at two levels. First, it inhibits the generation of plasmacytoid dendritic cells (pDCs), a major producer of IFN-αβ, from CD34+ hematopoietic progenitors. Second, it inhibits IFN-α release by immature pDCs exposed to influenza virus. Neutralization of endogenous TNF sustains IFN-α secretion by pDCs. These findings are clinically relevant, as five of five patients with systemic juvenile arthritis treated with TNF antagonists display overexpression of IFN-α-regulated genes in their blood leukocytes. These results, therefore, might provide a mechanistic explanation for the development of anti-dsDNA antibodies and lupus-like syndrome in patients undergoing anti-TNF therapy.

Original languageEnglish (US)
Pages (from-to)3372-3377
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number9
DOIs
StatePublished - Mar 1 2005
Externally publishedYes

Fingerprint

Dendritic Cells
Autoimmune Diseases
Juvenile Arthritis
Allergy and Immunology
Orthomyxoviridae
Autoimmunity
Systemic Lupus Erythematosus
Anti-Idiotypic Antibodies
Rheumatoid Arthritis
Leukocytes
Cytokines
Therapeutics
Genes
In Vitro Techniques

Keywords

  • Autoimmunity
  • Cytokines
  • Dendritic cells

ASJC Scopus subject areas

  • General

Cite this

Cross-regulation of TNF and IFN-α in autoimmune diseases. / Palucka, A. Karolina; Blanck, Jean Philippe; Bennett, Lynda; Pascual, Virginia; Banchereau, Jacques.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 102, No. 9, 01.03.2005, p. 3372-3377.

Research output: Contribution to journalArticle

Palucka, A. Karolina ; Blanck, Jean Philippe ; Bennett, Lynda ; Pascual, Virginia ; Banchereau, Jacques. / Cross-regulation of TNF and IFN-α in autoimmune diseases. In: Proceedings of the National Academy of Sciences of the United States of America. 2005 ; Vol. 102, No. 9. pp. 3372-3377.
@article{afdce2563e224069bab4f90929a0a42c,
title = "Cross-regulation of TNF and IFN-α in autoimmune diseases",
abstract = "Cytokines, most particularly TNF and type I IFN (IFN-αβ), have been long considered essential elements in the development of autoimmunity. Identification of TNF in the pathogenesis of rheumatoid arthritis and TNF antagonist therapy represent successes of immunology. IFN-αβ plays a major role in systemic lupus erythematosus (SLE), a prototype autoimmune disease characterized by a break of tolerance to nuclear components. Here, we show that TNF regulates IFN-α production in vitro at two levels. First, it inhibits the generation of plasmacytoid dendritic cells (pDCs), a major producer of IFN-αβ, from CD34+ hematopoietic progenitors. Second, it inhibits IFN-α release by immature pDCs exposed to influenza virus. Neutralization of endogenous TNF sustains IFN-α secretion by pDCs. These findings are clinically relevant, as five of five patients with systemic juvenile arthritis treated with TNF antagonists display overexpression of IFN-α-regulated genes in their blood leukocytes. These results, therefore, might provide a mechanistic explanation for the development of anti-dsDNA antibodies and lupus-like syndrome in patients undergoing anti-TNF therapy.",
keywords = "Autoimmunity, Cytokines, Dendritic cells",
author = "Palucka, {A. Karolina} and Blanck, {Jean Philippe} and Lynda Bennett and Virginia Pascual and Jacques Banchereau",
year = "2005",
month = "3",
day = "1",
doi = "10.1073/pnas.0408506102",
language = "English (US)",
volume = "102",
pages = "3372--3377",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "9",

}

TY - JOUR

T1 - Cross-regulation of TNF and IFN-α in autoimmune diseases

AU - Palucka, A. Karolina

AU - Blanck, Jean Philippe

AU - Bennett, Lynda

AU - Pascual, Virginia

AU - Banchereau, Jacques

PY - 2005/3/1

Y1 - 2005/3/1

N2 - Cytokines, most particularly TNF and type I IFN (IFN-αβ), have been long considered essential elements in the development of autoimmunity. Identification of TNF in the pathogenesis of rheumatoid arthritis and TNF antagonist therapy represent successes of immunology. IFN-αβ plays a major role in systemic lupus erythematosus (SLE), a prototype autoimmune disease characterized by a break of tolerance to nuclear components. Here, we show that TNF regulates IFN-α production in vitro at two levels. First, it inhibits the generation of plasmacytoid dendritic cells (pDCs), a major producer of IFN-αβ, from CD34+ hematopoietic progenitors. Second, it inhibits IFN-α release by immature pDCs exposed to influenza virus. Neutralization of endogenous TNF sustains IFN-α secretion by pDCs. These findings are clinically relevant, as five of five patients with systemic juvenile arthritis treated with TNF antagonists display overexpression of IFN-α-regulated genes in their blood leukocytes. These results, therefore, might provide a mechanistic explanation for the development of anti-dsDNA antibodies and lupus-like syndrome in patients undergoing anti-TNF therapy.

AB - Cytokines, most particularly TNF and type I IFN (IFN-αβ), have been long considered essential elements in the development of autoimmunity. Identification of TNF in the pathogenesis of rheumatoid arthritis and TNF antagonist therapy represent successes of immunology. IFN-αβ plays a major role in systemic lupus erythematosus (SLE), a prototype autoimmune disease characterized by a break of tolerance to nuclear components. Here, we show that TNF regulates IFN-α production in vitro at two levels. First, it inhibits the generation of plasmacytoid dendritic cells (pDCs), a major producer of IFN-αβ, from CD34+ hematopoietic progenitors. Second, it inhibits IFN-α release by immature pDCs exposed to influenza virus. Neutralization of endogenous TNF sustains IFN-α secretion by pDCs. These findings are clinically relevant, as five of five patients with systemic juvenile arthritis treated with TNF antagonists display overexpression of IFN-α-regulated genes in their blood leukocytes. These results, therefore, might provide a mechanistic explanation for the development of anti-dsDNA antibodies and lupus-like syndrome in patients undergoing anti-TNF therapy.

KW - Autoimmunity

KW - Cytokines

KW - Dendritic cells

UR - http://www.scopus.com/inward/record.url?scp=14744276518&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=14744276518&partnerID=8YFLogxK

U2 - 10.1073/pnas.0408506102

DO - 10.1073/pnas.0408506102

M3 - Article

C2 - 15728381

AN - SCOPUS:14744276518

VL - 102

SP - 3372

EP - 3377

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 9

ER -