Association of cytokine gene polymorphisms and the release of cytokines from peripheral blood mononuclear cells treated with methotrexate and dexamethasone.
Immunosuppressive drugs are widely used in the therapy of autoimmune disorders to suppress autoreactive T cells. The immune system is regulated by the release of cytokines. Cytokine are potent immunomodulatory molecules that act as mediators of inflammation and the immune response. Primarily secreted by T cell and macrophages, they influence cellular activation, differentiation, and function. Cytokine production is under genetic control. This is evidenced by the identification of polymorphism in cytokine gene regulatory regions that correlate with intra-individual variations in actual cytokine production. The aim of the study was to examine whether the individual differences in the polymorphic cytokine genes can lead to individual variation in release of cytokines after treatment with methotrexate and glucocorticosteroids. The study was carried out on mononuclear cells isolated from peripheral blood of 72 healthy subjects. The cells were activated with PHA and incubated with increasing concentrations of methotrexate (0.1-10 microM) and dexamethasone (0.01-1 microM). Levels of IL-2, IL-4, IL-6, IL-10, and TNFalpha in the culture supernatants were quantified by flow-cytometry using Th1/Th2 kit and correlated with cytokine gene polymorphisms. The increased concentrations of DEX resulted in comparable cytokine concentrations in cultures from subjects with low and high cytokine genotypes. Despite MTX treatment, the cytokine levels were significantly increased in individuals homozygous for the high producer allele. These results suggest that the cytokine gene variants may influence the efficacy of therapy with some immunosuppressive and anti-inflammatory drugs.
Pawlik
A
A
Department of Pharmacokinetics and Therapeutic Drug Monitoring, Pomeranian Medical University, 70-111 Szczecin, ul. Powst. Wlkp. 72, Poland. pawand@poczta.onet.pl
Baskiewicz-Masiuk
M
M
Machalinski
B
B
Gawronska-Szklarz
B
B
D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism; D008727:Methotrexate / Q000494:pharmacology*; D011110:Polymorphism, Genetic
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D007166:Immunosuppressive Agents; D003907:Dexamethasone; D008727:Methotrexate