Impact of topoisomerase II inhibition on cytokine and chemokine production.
OBJECTIVE
In systemic inflammatory diseases such as rheumatoid arthritis, cytokines and chemokines are deeply involved in the development of the disease manifestations. Etoposide is a cytostatic drug, known to deplete the monocyte population in mice and rabbits. We have recently shown that suboptimal doses have a disease-ameliorating effect in collagen II induced arthritis in the absence of monocyte depletion. Anti-arthritic properties parallelled with almost total eradication of production of specific collagen II antibodies. The aim of the present study was to investigate ex vivo and in vitro the function of the mononuclear cells and their production of B cell stimulating cytokines following exposure to etoposide, a topoisomerase II inhibitor.


METHODS
Spleen cells from mice treated during four weeks with etoposide were cultured and the supernatants were analyzed with respect to content of TNF and IL-6. In addition, cells from the murine macrophage cell clone IC-21 were exposed to etoposide and the production of IL-6, using a bioassay, and the production of TNF, MIP-1alpha, RANTES, and IL-1beta, using sandwich ELISAs, was determined.


RESULTS
Spleen cells from etoposide-treated mice secreted lower amounts of IL-6 and TNF as compared to the control animals. In addition, in vitro etoposide-exposed macrophages showed reduced capacity to produce TNF, IL-6 and MIP-1alpha.


CONCLUSIONS
Our results indicate that inhibition of topoisomerase II downregulated the function of monocytes. Owing to its immunoregulatory properties, use of etoposide is suggested in treatment of chronic inflammatory diseases.
Verdrengh
M
M
Department of Rheumatology and Inflammation Research, Göteborg University, Guldhedsgatan 10A, SE-413 46 Göteborg, Sweden. margareta.verdrengh@rheuma.gu.se
Tarkowski
A
A
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000378:metabolism; D018925:Chemokines / Q000096:biosynthesis*; D016207:Cytokines / Q000096:biosynthesis*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D007371:Interferon-gamma / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D007958:Leukocyte Count; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis; D051379:Mice; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D059005:Topoisomerase II Inhibitors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000972:Antineoplastic Agents, Phytogenic; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D018925:Chemokines; D016207:Cytokines; D004791:Enzyme Inhibitors; D015850:Interleukin-6; D019402:Macrophage Inflammatory Proteins; D059005:Topoisomerase II Inhibitors; D014409:Tumor Necrosis Factor-alpha; D005047:Etoposide; D007371:Interferon-gamma