Hyaluronic acid-specific regulation of cytokines by human uterine fibroblasts.

The physiological inflammatory response can provide an effective mechanism for delivering the baby at the time of parturition. We characterized the mechanisms by which hyaluronic acid (HA) regulates interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), and interleukin-8 (IL-8) production in human uterine fibroblasts. A dose-dependent increase in cytokine release was observed over an HA concentration range of 10 microg/ml to 1 mg/ml. The action of HA on the cytokine production is mediated by CD44. Under serum-free conditions, HA-induced cytokine generation was significantly less compared with production in the presence of serum, suggesting involvement of serum proteins. Addition of inter-alpha-trypsin inhibitor (ITI) under serum-free conditions enhanced the HA-induced synthesis of TNF-alpha, which stimulated the temporary release of IL-8. In addition, HA and IL-1beta stimulated the release of hyaluronidase by the fibroblasts. These results indicate that cytokine production in human uterine fibroblasts is regulated in a CD44-HA-ITI-specific fashion. HA may be involved in the regulation of delivery in part through the selective release of cytokines that contribute to uterine cervical ripening.