Hyaluronan fragments synergize with interferon-gamma to induce the C-X-C chemokines Mig and interferon-inducible protein-10 in mouse macrophages

Hallmarks of chronic inflammation and tissue fibrosis are increased influx of activated inflammatory cells, mediator release, and increased turnover a nd production of the extracellular matrix (ECM). Recent evidence has sugges ted that fragments of the ECM component hyaluronan play a role in chronic i nflammation by inducing macrophage expression of chemokines. Interferon-gam ma (IFN-gamma), an important regulator of macrophage functions, has been sh own to induce the C-X-C chemokines Mig and IP-10. These chemokines affect T -cell recruitment and inhibit angiogenesis. The purpose of this investigati on 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 betwee n HA and IFN-gamma on Mig and IP-10 mRNA and protein expression in mouse ma crophages. 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 sy nthesis, was not mediated by tumor necrosis factor-cy, was selective for Mi g and IP-10, and occurred at the level of gene transcription. These data su ggest that the ECM component HA may influence chronic inflammatory states b y working in concert with IFN-gamma to alter macrophage chemokine expressio n.