Submitted February 9, 2009
Accepted April 21, 2009
Identification of crassin acetate as a new immunosuppressant triggering heme oxygenase-1 expression in dendritic cells
Hironori Matsushima, Hiroaki Tanaka, Norikatsu Mizumoto, and Akira Takashima*
Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, TX, United States
Department of Medical Microbiology and Immunology, University of Toledo College of Medicine, Toledo, OH, United States
* Corresponding author; email: akira.takashima{at}utoledo.edu.
By screening 720 natural compounds in a standard two-way allogeneic mixed leukocyte reaction (allo-MLR) assay, we identified a potent immunosuppressive capacity of crassin acetate (CRA), a coral-derived cembrane diterpenoid. CRA efficiently inhibited allo-MLR as well as antigen-specific activation of CD4 T cells by bone marrow-derived dendritic cells (DCs). With regard to cellular targets, CRA suppressed not only mitogen-triggered T cell activation, but also lipopolysaccharide (LPS)-induced DC maturation, indicating dual functionality. Treatment with CRA at non-toxic doses induced heme oxygenase-1 (HO-1) mRNA/protein expression and HO-1 enzymatic activity in DCs, suggesting a unique mechanism of action. In fact, LPS-induced DC maturation was also inhibited by structurally unrelated compounds known to induce HO-1 expression or carbon monoxide release. Allergic contact hypersensitivity response to oxazolone (OX) and OX-induced Langerhans cell migration from epidermis were both prevented almost completely by systemic administration of CRA. Not only do our results support the recent concept that HO-1/CO system negatively regulates immune responses, they also form both conceptual and technical frameworks for a more systematic, large-scale drug discovery effort to identify HO-1/CO-targeted immunosuppressants with dual target specificity.
