ABSTRACT
Cyclophilin A (CypA), an 18 kDa multi-functional protein with cis-trans isomerase activity, is both a ligand for cyclosporine A and a proinflammatory factor. CypA is also a chemoattractant for hemopoietic stem cells and progenitors of different lineages, and can mediate regenerative processes in an organism. Accumulated experimental data have suggested there are practical applications for this protein in the treatment of several diseases (i.e. neutralization of cyclosporine A side effects, etc.). However, the range of CypA safe doses as well as its toxic effects remain unknown. The study here investigated the acute toxicity of a single intraperitoneal (IP) or subcutaneous (SC) dosing of recombinant human CypA (rhCypA) in both female and male mice and its effect on gene expression of acute phase proteins (APP) in the female mice after IP treatment. The results showed that toxicity of rhCypA was most evident in female and male mice dosed IP with 750 mg/kg, and manifested as kidney injury and increased granulocyte/lymphocyte ratios in the blood. Enhanced expression of Sаа1 and Sаа2 genes was induced with doses of 0.1-2 mg/mouse of rhCypA. Injection of the maximal dose (750 mg/kg) significantly stimulated expression of all the APP genes studied.
Subject(s)
Acute Kidney Injury/chemically induced , Acute-Phase Proteins/metabolism , Cyclophilin A/toxicity , Toxicity Tests, Acute , Acute Kidney Injury/blood , Acute Kidney Injury/immunology , Acute-Phase Proteins/immunology , Animals , Cyclophilin A/administration & dosage , Cyclophilin A/isolation & purification , Disease Models, Animal , Dose-Response Relationship, Drug , Female , Gene Expression/drug effects , Gene Expression/immunology , Gene Expression Profiling , Granulocytes , Humans , Injections, Intraperitoneal , Injections, Subcutaneous , Kidney/drug effects , Kidney/immunology , Kidney/pathology , Lethal Dose 50 , Lymphocyte Count , Male , Mice , Recombinant Proteins/administration & dosage , Recombinant Proteins/isolation & purification , Recombinant Proteins/toxicityABSTRACT
Supernatant obtained from high dose hydrocortisone resistant thymocytes can induce migration of the bone marrow cell precursors to the periphery. This biological activity depends on the presence of the 18 kDa protein, whose amino acid sequence fits with the sequence of the secretory form of murine cyclophilin A (SP-18). Cyclophilin A isolated from the supernatant of the cortisone-resistant thymoma EL-4 shows its characteristic functional features as it demonstrates isomerase activity and binds with cyclosporine A. The cyclophilin A obtained manifests chemotactic activity that regulates migration of bone marrow cell precursors of neutrophils, T-, B- and dendritic cells.
