Hyaluronan Fragments Synergize with Interferon-γ to Induce the C-X-C Chemokines Mig and Interferon-inducible Protein-10 in Mouse Macrophages

Maureen R Horton,Charlotte M Mckee,Clare Bao,Fang Liao,Joshua M Farber,Jennifer Hodge-Dufour,Ellen Puré,Bonnie L Oliver,Timothy M Wright,Paul W Noble

doi:10.1074/jbc.273.52.35088

Maureen R Horton, Charlotte M Mckee + Show 8 more

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https://doi.org/10.1074/jbc.273.52.35088

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Abstract

Hallmarks of chronic inflammation and tissue fibrosis are increased influx of activated inflammatory cells, mediator release, and increased turnover and production of the extracellular matrix (ECM). Recent evidence has suggested that fragments of the ECM component hyaluronan play a role in chronic inflammation by inducing macrophage expression of chemokines. Interferon-gamma (IFN-gamma), an important regulator of macrophage functions, has been shown to induce the C-X-C chemokines Mig and IP-10. These chemokines affect T-cell recruitment and inhibit angiogenesis. The purpose of this investigation was to determine the effect of hyaluronan (HA) on IFN-gamma-induced Mig and IP-10 expression in mouse macrophages. We found a marked synergy between HA and IFN-gamma on Mig and IP-10 mRNA and protein expression in mouse macrophages. This was most significant with Mig, which was not induced by HA alone. The synergy was specific for HA, was not dependent on new protein synthesis, was not mediated by tumor necrosis factor-alpha, was selective for Mig and IP-10, and occurred at the level of gene transcription. These data suggest that the ECM component HA may influence chronic inflammatory states by working in concert with IFN-gamma to alter macrophage chemokine expression.

Highlights

Hallmarks of chronic inflammation and tissue fibrosis are increased influx of activated inflammatory cells, mediator release, and increased turnover and production of the extracellular matrix (ECM)
HA Fragments Synergize with IFN␥ to Induce Mig and inducible protein-10 (IP-10) mRNA Expression in Mouse Macrophages—We investigated the effect of HA and IFN-␥ on Mig and IP-10 mRNA expression by mouse macrophages
Mig and IP-10 were originally identified as being induced by IFN-␥ stimulation of the mouse macrophage cell line RAW 264.7 [25, 26]

Summary

Introduction

Hallmarks of chronic inflammation and tissue fibrosis are increased influx of activated inflammatory cells, mediator release, and increased turnover and production of the extracellular matrix (ECM). Interferon-␥ (IFN-␥), an important regulator of macrophage functions, has been shown to induce the C-X-C chemokines Mig and IP-10 These chemokines affect T-cell recruitment and inhibit angiogenesis. The synergy was specific for HA, was not dependent on new protein synthesis, was not mediated by tumor necrosis factor-␣, was selective for Mig and IP-10, and occurred at the level of gene transcription These data suggest that the ECM component HA may influence chronic inflammatory states by working in concert with IFN-␥ to alter macrophage chemokine expression. Recent studies have suggested that these lower molecular weight forms of HA may stimulate macrophages recruited to sites of inflammation to produce important mediators of tissue injury and repair [13,14,15,16]. Recent investigations have described synergistic enhancement of IFN-␥-induced Mig and IP-10 expression by TNF-␣ in fibroblasts [40, 41]

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