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 Blood, 2 July 2009, Vol. 114, No. 1, pp. 64-73.
Prepublished online as a Blood First Edition Paper on April 28, 2009; DOI 10.1182/blood-2009-02-204297.

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IMMUNOBIOLOGY

Identification of crassin acetate as a new immunosuppressant triggering heme oxygenase-1 expression in dendritic cells

Hironori Matsushima1,2, Hiroaki Tanaka1, Norikatsu Mizumoto1, and Akira Takashima1,2

1 Department of Dermatology, University of Texas Southwestern Medical Center, Dallas; and 2 Department of Medical Microbiology and Immunology, University of Toledo College of Medicine, OH

By screening 720 natural compounds in a standard 2-way allogeneic mixed leukocyte reaction assay, we identified a potent immunosuppressive capacity of crassin acetate (CRA), a coral-derived cembrane diterpenoid. CRA efficiently inhibited allogeneic mixed leukocyte reaction 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-induced DC maturation, indicating dual functionality. Treatment with CRA at nontoxic 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, lipopolysaccharide-induced DC maturation was also inhibited by structurally unrelated compounds known to induce HO-1 expression or carbon monoxide (CO) release. Allergic contact hypersensitivity response to oxazolone and oxazolone-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.


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