Activation and transforming growth factor-beta production in eosinophils by hyaluronan

To investigate whether extracellular matrix glycosaminoglycan hyaluronan (H A) modulates eosinophil activation and transforming growth factor (TGF)-bet a production by eosinophils, human peripheral blood eosinophils (purity > 9 9%) from 12 patients with mild to moderate asthma or six healthy subjects w ere isolated and incubated with increasing concentrations of low molecular weight (mol wt) HA (approximate to 0.2 x 10(6) D) or high mol wt HA (3.0 to approximate to 5.8 x 10(6) D). We found that the low mol wt HA has a prono unced effect on eosinophil survival in both patients with asthma and health y subjects in a dose-dependent fashion on Days 2 and 4. Whereas the high mo l wt HA had a smaller effect on eosinophil survival than did the low mol wt HA. The HA-mediated eosinophil survival was partially but significantly in hibited ( approximate to 50% inhibition) by a blocking monoclonal antibody for CD44, a specific receptor of HA, and largely inhibited by an anti-granu locyte macrophage colony-stimulating factor (CM-CSF) neutralizing antibody but not by an anti-interleukin (IL)-3 or anti-IL-5 neutralizing antibody. I n addition, the low mol wt HA increased CM-CSF messenger RNA (mRNA) express ion and protein secretion by eosinophils in a dose-dependent fashion, sugge sting that the HA-mediated eosinophil survival is due mainly to induction o f CM-CSF release through partial CD44 signaling. Furthermore, we demonstrat ed that the low mol wt HA results in morphologic changes in eosinophils suc h as transforming from a round to a spindle shape and in homotypic aggregat ion, upregulates intercellular adhesion molecule-1 expression, and increase s TGF-beta mRNA expression and protein secretion by eosinophils. These obse rvations suggest previously unforeseen interactions between eosinophils and low mot wt extracellular matrix and, thus, novel pathways by which eosinop hils may contribute to the regulation of airway inflammation and airway re- modeling.