Hyaluronic acid-specific regulation of cytokines by human uterine fibroblasts

The physiological inflammatory response can provide an effectivemechanism for delivering the baby at the time of parturition. Wecharacterized the mechanisms by which hyaluronic acid (HA) regulatesinterleukin-1 (IL-1), tumor necrosis factor- (TNF-), andinterleukin-8 (IL-8) production in human uterine fibroblasts. Adose-dependent increase in cytokine release was observed over an HAconcentration range of 10 µg/ml to 1 mg/ml. The action of HA on thecytokine production is mediated by CD44. Under serum-free conditions,HA-induced cytokine generation was significantly less compared withproduction in the presence of serum, suggesting involvement of serumproteins. Addition of inter--trypsin inhibitor (ITI) underserum-free conditions enhanced the HA-induced synthesis of TNF-,which stimulated the temporary release of IL-8. In addition, HA andIL-1 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 beinvolved in the regulation of delivery in part through the selectiverelease of cytokines that contribute to uterine cervical ripening.