HYALURONAN FRAGMENTS INDUCE NITRIC-OXIDE SYNTHASE IN MURINE MACROPHAGES THROUGH A NUCLEAR FACTOR KAPPA-B-DEPENDENT MECHANISM

Activated macrophages play a critical role in controlling chronic tiss ue inflammation through the release of a variety of mediators includin g cytokines, chemokines, growth factors, active lipids, reactive oxyge n, and nitrogen species, The mechanisms that regulate macrophage activ ation in chronic inflammation are poorly understood, A hallmark of chr onic inflammation is the turnover of extracellular matrix components, and recent work has suggested that interactions with the extracellular matrix can exert important influences on macrophage effector function s, We have examined the effect of low molecular weight fragments of th e extracellular matrix glycosaminoglycan hyaluronan (HA) on the induct ion of nitric-oxide synthase (iNOS) in macrophages. We found that HA f ragments induce iNOS mRNA, protein and activity alone, and markedly sy nergize with interferon-gamma to induce iNOS gene expression in murine macrophages. In addition, we found that resident tissue alveolar macr ophages respond minimally, but inflammatory alveolar macrophages exhib it a marked induction in iNOS expression in response to HA fragments, Finally, we demonstrate that the mechanism of HA fragment-induced expr ession of iNOS requires activation of the transcriptional regulator nu clear factor kappa B, These data support the hypothesis that HA may be an important regulator of macrophage activation at sites of chronic t issue inflammation.