The molecular basis for the immunomodulatory activities of unconjugated bilirubin

Nearly a century ago, jaundiced patients were observed to have surprising and spontaneous remissions from incurable immunologic diseases including rheumatoid arthritis, allergy, and asthma. The mystery of why this phenomenon occurred remains unresolved to this day. Bilirubin has traditionally been considered an excretory product resulting from heme metabolism with little benefit to human physiology. In the past few decades, however, the salutary role of this byproduct as a potent antioxidant has been repeatedly noted. Most recently, the molecule has been found to possess immunomodulatory properties that rival its redox capacity, possibly explaining its ability to suppress inflammation. In this review, we specifically examine unconjugated bilirubin (UCB) as an immunomodulator and explore the molecular basis for its immunosuppressive effects.