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

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this