title: Novel immunosuppressive agent caerulomycin A exerts its effect by depleting cellular iron content.
abstract: OBJECTIVE
  Recently, we have described the use of caerulomycin A (CaeA) as a potent novel immunosuppressive agent. Immunosuppressive drugs are crucial for long-term graft survival following organ transplantation and treatment of autoimmune diseases, inflammatory disorders, hypersensitivity to allergens, etc. The objective of this study was to identify cellular targets of CaeA and decipher its mechanism of action.
  
  
  METHODS
  Jurkat cells were treated with CaeA and cellular iron content, iron uptake/release, DNA content and deoxyribonucleoside triphosphate pool determined. Activation of MAPKs; expression level of transferrin receptor 1, ferritin and cell cycle control molecules; reactive oxygen species (ROS) and cell viability were measured using Western blotting, qRT-PCR or flow cytometry.
  
  
  RESULTS
  CaeA caused intracellular iron depletion by reducing its uptake and increasing its release by cells. CaeA caused cell cycle arrest by (i) inhibiting ribonucleotide reductase (RNR) enzyme, which catalyses the rate-limiting step in the synthesis of DNA; (ii) stimulating MAPKs signalling transduction pathways that play an important role in cell growth, proliferation and differentiation; and (iii) by targeting cell cycle control molecules such as cyclin D1, cyclin-dependent kinase 4 and p21(CIP1/WAF1) . The effect of CaeA on cell proliferation was reversible.
  
  
  CONCLUSIONS
  CaeA exerts its immunosuppressive effect by targeting iron. The effect is reversible, which makes CaeA an attractive candidate for development as a potent immunosuppressive drug, but also indicates that iron chelation can be used as a rationale approach to selectively suppress the immune system, because compared with normal cells, rapidly proliferating cells require a higher utilization of iron.
authors.affiliation: Department of Chemistry, CSIR-Institute of Microbial Technology, Chandigarh, India.
authors.forename: Suneet
authors.initials: S
authors.lastname: Kaur
authors.forename: Gautam
authors.initials: G
authors.lastname: Srivastava
authors.forename: Amar Nath
authors.initials: AN
authors.lastname: Sharma
authors.forename: Ravinder S
authors.initials: RS
authors.lastname: Jolly
mesh_terms: D015703:Antigens, CD / Q000187:drug effects / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005293:Ferritins / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000494:pharmacology*; D019169:Jurkat Cells; D020935:MAP Kinase Signaling System / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D011990:Receptors, Transferrin / Q000187:drug effects / Q000378:metabolism; D012262:Ribonucleoside Diphosphate Reductase / Q000037:antagonists & inhibitors / Q000378:metabolism; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
chemical_list: D015703:Antigens, CD; C068126:CD71 antigen; D018797:Cell Cycle Proteins; D007166:Immunosuppressive Agents; D007502:Iron Chelating Agents; D011725:Pyridines; D011990:Receptors, Transferrin; C544423:caerulomycin A; D005293:Ferritins; D007501:Iron; C093713:ribonucleotide reductase M2; D012262:Ribonucleoside Diphosphate Reductase