Hyaluronan fragments activate an NF-κB/I-κBα autoregulatory loop in murine macrophages

Paul W. Noble, Charlotte M. McKee, Mary Cowman, Hyun S. Shin

Research output: Contribution to journalArticle

Abstract

Macrophages play an important role in the acute tissue inflammatory response through the release of cytokines and growth factors in response to stimuli such as lipopolysaccharide (LPS). Macrophage inflammatory effector functions are also influenced by interactions with the extracellular matrix (ECM). Such macrophage-ECM interactions may be important in regulating chronic inflammatory responses. Recent evidence has suggested that hyaluronan (HA), a glycosaminoglycan (GAG) component of ECM can induce inflammatory gene expression in murine macrophages. HA exists in its native form as a large polymer, but is found as smaller fragments under inflammatory conditions. The NF-κB/I-κB transcriptional regulatory system has been shown to be a critical component of the host inflammatory response. We examined the effects of high molecular weight HA and lower molecular weigh HA fragments on NF-κB activation in mouse macrophages. Only the smaller HA fragments were found to activate NF-κB DNA binding activity. After HA stimulation, I-κBα mRNA was induced and I-κBα protein levels, which initially decrease, were restored. The induction of I-κBα expression was not observed for other GAGs. The time course of I-kBα protein regeneration in response to HA fragments was consistent with an autoregulatory mechanism, in support of this mechanism, in vitro translated murine I-κBα inhibited HA fragment-induced NF-kB DNA binding activity. The NF-κB DNA binding complex in HA-stimulated extracts was found to contain p50 and p65 subunits. Activation of the NF-κB/I-κB system in macrophages by ECM fragments may be an important mechanism for propagating the tissue inflammatory response.

Original languageEnglish (US)
Pages (from-to)2373-2378
Number of pages6
JournalJournal of Experimental Medicine
Volume183
Issue number5
DOIs
StatePublished - May 1 1996

Fingerprint

Hyaluronic Acid
Macrophages
Extracellular Matrix
DNA
NF-kappa B
Glycosaminoglycans
Lipopolysaccharides
Regeneration
Intercellular Signaling Peptides and Proteins
Polymers
Molecular Weight
Cytokines
Gene Expression
Messenger RNA

ASJC Scopus subject areas

  • Immunology

Cite this

Hyaluronan fragments activate an NF-κB/I-κBα autoregulatory loop in murine macrophages. / Noble, Paul W.; McKee, Charlotte M.; Cowman, Mary; Shin, Hyun S.

In: Journal of Experimental Medicine, Vol. 183, No. 5, 01.05.1996, p. 2373-2378.

Research output: Contribution to journalArticle

Noble, Paul W. ; McKee, Charlotte M. ; Cowman, Mary ; Shin, Hyun S. / Hyaluronan fragments activate an NF-κB/I-κBα autoregulatory loop in murine macrophages. In: Journal of Experimental Medicine. 1996 ; Vol. 183, No. 5. pp. 2373-2378.
@article{d76922a475574cf19986948b8ff91180,
title = "Hyaluronan fragments activate an NF-κB/I-κBα autoregulatory loop in murine macrophages",
abstract = "Macrophages play an important role in the acute tissue inflammatory response through the release of cytokines and growth factors in response to stimuli such as lipopolysaccharide (LPS). Macrophage inflammatory effector functions are also influenced by interactions with the extracellular matrix (ECM). Such macrophage-ECM interactions may be important in regulating chronic inflammatory responses. Recent evidence has suggested that hyaluronan (HA), a glycosaminoglycan (GAG) component of ECM can induce inflammatory gene expression in murine macrophages. HA exists in its native form as a large polymer, but is found as smaller fragments under inflammatory conditions. The NF-κB/I-κB transcriptional regulatory system has been shown to be a critical component of the host inflammatory response. We examined the effects of high molecular weight HA and lower molecular weigh HA fragments on NF-κB activation in mouse macrophages. Only the smaller HA fragments were found to activate NF-κB DNA binding activity. After HA stimulation, I-κBα mRNA was induced and I-κBα protein levels, which initially decrease, were restored. The induction of I-κBα expression was not observed for other GAGs. The time course of I-kBα protein regeneration in response to HA fragments was consistent with an autoregulatory mechanism, in support of this mechanism, in vitro translated murine I-κBα inhibited HA fragment-induced NF-kB DNA binding activity. The NF-κB DNA binding complex in HA-stimulated extracts was found to contain p50 and p65 subunits. Activation of the NF-κB/I-κB system in macrophages by ECM fragments may be an important mechanism for propagating the tissue inflammatory response.",
author = "Noble, {Paul W.} and McKee, {Charlotte M.} and Mary Cowman and Shin, {Hyun S.}",
year = "1996",
month = "5",
day = "1",
doi = "10.1084/jem.183.5.2373",
language = "English (US)",
volume = "183",
pages = "2373--2378",
journal = "Journal of Experimental Medicine",
issn = "0022-1007",
publisher = "Rockefeller University Press",
number = "5",

}

TY - JOUR

T1 - Hyaluronan fragments activate an NF-κB/I-κBα autoregulatory loop in murine macrophages

AU - Noble, Paul W.

AU - McKee, Charlotte M.

AU - Cowman, Mary

AU - Shin, Hyun S.

PY - 1996/5/1

Y1 - 1996/5/1

N2 - Macrophages play an important role in the acute tissue inflammatory response through the release of cytokines and growth factors in response to stimuli such as lipopolysaccharide (LPS). Macrophage inflammatory effector functions are also influenced by interactions with the extracellular matrix (ECM). Such macrophage-ECM interactions may be important in regulating chronic inflammatory responses. Recent evidence has suggested that hyaluronan (HA), a glycosaminoglycan (GAG) component of ECM can induce inflammatory gene expression in murine macrophages. HA exists in its native form as a large polymer, but is found as smaller fragments under inflammatory conditions. The NF-κB/I-κB transcriptional regulatory system has been shown to be a critical component of the host inflammatory response. We examined the effects of high molecular weight HA and lower molecular weigh HA fragments on NF-κB activation in mouse macrophages. Only the smaller HA fragments were found to activate NF-κB DNA binding activity. After HA stimulation, I-κBα mRNA was induced and I-κBα protein levels, which initially decrease, were restored. The induction of I-κBα expression was not observed for other GAGs. The time course of I-kBα protein regeneration in response to HA fragments was consistent with an autoregulatory mechanism, in support of this mechanism, in vitro translated murine I-κBα inhibited HA fragment-induced NF-kB DNA binding activity. The NF-κB DNA binding complex in HA-stimulated extracts was found to contain p50 and p65 subunits. Activation of the NF-κB/I-κB system in macrophages by ECM fragments may be an important mechanism for propagating the tissue inflammatory response.

AB - Macrophages play an important role in the acute tissue inflammatory response through the release of cytokines and growth factors in response to stimuli such as lipopolysaccharide (LPS). Macrophage inflammatory effector functions are also influenced by interactions with the extracellular matrix (ECM). Such macrophage-ECM interactions may be important in regulating chronic inflammatory responses. Recent evidence has suggested that hyaluronan (HA), a glycosaminoglycan (GAG) component of ECM can induce inflammatory gene expression in murine macrophages. HA exists in its native form as a large polymer, but is found as smaller fragments under inflammatory conditions. The NF-κB/I-κB transcriptional regulatory system has been shown to be a critical component of the host inflammatory response. We examined the effects of high molecular weight HA and lower molecular weigh HA fragments on NF-κB activation in mouse macrophages. Only the smaller HA fragments were found to activate NF-κB DNA binding activity. After HA stimulation, I-κBα mRNA was induced and I-κBα protein levels, which initially decrease, were restored. The induction of I-κBα expression was not observed for other GAGs. The time course of I-kBα protein regeneration in response to HA fragments was consistent with an autoregulatory mechanism, in support of this mechanism, in vitro translated murine I-κBα inhibited HA fragment-induced NF-kB DNA binding activity. The NF-κB DNA binding complex in HA-stimulated extracts was found to contain p50 and p65 subunits. Activation of the NF-κB/I-κB system in macrophages by ECM fragments may be an important mechanism for propagating the tissue inflammatory response.

UR - http://www.scopus.com/inward/record.url?scp=0029952227&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0029952227&partnerID=8YFLogxK

U2 - 10.1084/jem.183.5.2373

DO - 10.1084/jem.183.5.2373

M3 - Article

C2 - 8642348

AN - SCOPUS:0029952227

VL - 183

SP - 2373

EP - 2378

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

SN - 0022-1007

IS - 5

ER -