Identification of crassin acetate as a new immunosuppressant triggering heme oxygenase-1 expression in dendritic cells.
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.
Matsushima
Hironori
H
Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Tanaka
Hiroaki
H
Mizumoto
Norikatsu
N
Takashima
Akira
A
D000818:Animals; D002248:Carbon Monoxide / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology* / Q000276:immunology; D004224:Diterpenes / Q000494:pharmacology* / Q000633:toxicity; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000235:genetics* / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000633:toxicity; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D004224:Diterpenes; D007166:Immunosuppressive Agents; D008070:Lipopolysaccharides; D012333:RNA, Messenger; C011424:crassin acetate; D002248:Carbon Monoxide; D051547:Heme Oxygenase-1