Loss of negative feedback control of nuclear factor-κB2 activity in lymphocytes leads to fatal lung inflammation

Liqun Yang, Hongjuan Cui, Zhe Wang, Baochun Zhang, Jane Ding, Lin Liu, Hanfei Ding

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Proteolytic processing of the nuclear factor (NF)-κB2 precursor protein p100 generates the active NF-κB2 subunit p52, which in turn transcriptionally up-regulates p100 expression. p100 also functions as an IκB molecule capable of repressing p52 activity. The biological significance of this negative feedback control loop has yet to be demonstrated in vivo. Here we show that mice deficient in p100 but with constitutive expression of p52 in lymphocytes developed fatal lung inflammation characterized by diffuse alveolar damage with marked peribronchial fibrosis. In contrast, their littermates with only p100 deficiency or constitutive expression of p52 in lymphocytes developed mild lung inflammation with perivascular lymphocyte infiltration and had a normal life span. The fatal lung inflammation is associated with high-level induction of interferon-γ and its inducible inflammatory chemokines, suggesting the involvement of a T-helper-1 immune response. These findings demonstrate the physiological relevance of the NF-κB2 p100 precursor protein in limiting the potentially detrimental effects of constitutive NF-κB2 signaling in lymphocytes.

Original languageEnglish (US)
Pages (from-to)2646-2657
Number of pages12
JournalAmerican Journal of Pathology
Volume176
Issue number6
DOIs
StatePublished - Jun 2010

Fingerprint

Pneumonia
Lymphocytes
Protein Precursors
Chemokines
Interferons
Fibrosis
Up-Regulation

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Loss of negative feedback control of nuclear factor-κB2 activity in lymphocytes leads to fatal lung inflammation. / Yang, Liqun; Cui, Hongjuan; Wang, Zhe; Zhang, Baochun; Ding, Jane; Liu, Lin; Ding, Hanfei.

In: American Journal of Pathology, Vol. 176, No. 6, 06.2010, p. 2646-2657.

Research output: Contribution to journalArticle

Yang, Liqun ; Cui, Hongjuan ; Wang, Zhe ; Zhang, Baochun ; Ding, Jane ; Liu, Lin ; Ding, Hanfei. / Loss of negative feedback control of nuclear factor-κB2 activity in lymphocytes leads to fatal lung inflammation. In: American Journal of Pathology. 2010 ; Vol. 176, No. 6. pp. 2646-2657.
@article{67e6a5a0f9a646639d8ecba49965a5a6,
title = "Loss of negative feedback control of nuclear factor-κB2 activity in lymphocytes leads to fatal lung inflammation",
abstract = "Proteolytic processing of the nuclear factor (NF)-κB2 precursor protein p100 generates the active NF-κB2 subunit p52, which in turn transcriptionally up-regulates p100 expression. p100 also functions as an IκB molecule capable of repressing p52 activity. The biological significance of this negative feedback control loop has yet to be demonstrated in vivo. Here we show that mice deficient in p100 but with constitutive expression of p52 in lymphocytes developed fatal lung inflammation characterized by diffuse alveolar damage with marked peribronchial fibrosis. In contrast, their littermates with only p100 deficiency or constitutive expression of p52 in lymphocytes developed mild lung inflammation with perivascular lymphocyte infiltration and had a normal life span. The fatal lung inflammation is associated with high-level induction of interferon-γ and its inducible inflammatory chemokines, suggesting the involvement of a T-helper-1 immune response. These findings demonstrate the physiological relevance of the NF-κB2 p100 precursor protein in limiting the potentially detrimental effects of constitutive NF-κB2 signaling in lymphocytes.",
author = "Liqun Yang and Hongjuan Cui and Zhe Wang and Baochun Zhang and Jane Ding and Lin Liu and Hanfei Ding",
year = "2010",
month = "6",
doi = "10.2353/ajpath.2010.090751",
language = "English (US)",
volume = "176",
pages = "2646--2657",
journal = "American Journal of Pathology",
issn = "0002-9440",
publisher = "Elsevier Inc.",
number = "6",

}

TY - JOUR

T1 - Loss of negative feedback control of nuclear factor-κB2 activity in lymphocytes leads to fatal lung inflammation

AU - Yang, Liqun

AU - Cui, Hongjuan

AU - Wang, Zhe

AU - Zhang, Baochun

AU - Ding, Jane

AU - Liu, Lin

AU - Ding, Hanfei

PY - 2010/6

Y1 - 2010/6

N2 - Proteolytic processing of the nuclear factor (NF)-κB2 precursor protein p100 generates the active NF-κB2 subunit p52, which in turn transcriptionally up-regulates p100 expression. p100 also functions as an IκB molecule capable of repressing p52 activity. The biological significance of this negative feedback control loop has yet to be demonstrated in vivo. Here we show that mice deficient in p100 but with constitutive expression of p52 in lymphocytes developed fatal lung inflammation characterized by diffuse alveolar damage with marked peribronchial fibrosis. In contrast, their littermates with only p100 deficiency or constitutive expression of p52 in lymphocytes developed mild lung inflammation with perivascular lymphocyte infiltration and had a normal life span. The fatal lung inflammation is associated with high-level induction of interferon-γ and its inducible inflammatory chemokines, suggesting the involvement of a T-helper-1 immune response. These findings demonstrate the physiological relevance of the NF-κB2 p100 precursor protein in limiting the potentially detrimental effects of constitutive NF-κB2 signaling in lymphocytes.

AB - Proteolytic processing of the nuclear factor (NF)-κB2 precursor protein p100 generates the active NF-κB2 subunit p52, which in turn transcriptionally up-regulates p100 expression. p100 also functions as an IκB molecule capable of repressing p52 activity. The biological significance of this negative feedback control loop has yet to be demonstrated in vivo. Here we show that mice deficient in p100 but with constitutive expression of p52 in lymphocytes developed fatal lung inflammation characterized by diffuse alveolar damage with marked peribronchial fibrosis. In contrast, their littermates with only p100 deficiency or constitutive expression of p52 in lymphocytes developed mild lung inflammation with perivascular lymphocyte infiltration and had a normal life span. The fatal lung inflammation is associated with high-level induction of interferon-γ and its inducible inflammatory chemokines, suggesting the involvement of a T-helper-1 immune response. These findings demonstrate the physiological relevance of the NF-κB2 p100 precursor protein in limiting the potentially detrimental effects of constitutive NF-κB2 signaling in lymphocytes.

UR - http://www.scopus.com/inward/record.url?scp=77953209851&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77953209851&partnerID=8YFLogxK

U2 - 10.2353/ajpath.2010.090751

DO - 10.2353/ajpath.2010.090751

M3 - Article

C2 - 20363924

AN - SCOPUS:77953209851

VL - 176

SP - 2646

EP - 2657

JO - American Journal of Pathology

JF - American Journal of Pathology

SN - 0002-9440

IS - 6

ER -