IL-1beta mediates diethyldithiocarbamate-induced granulocyte colony-stimulating factor production and hematopoiesis.
Diethyldithiocarbamate (DDTC) exhibits chemoprotective effects via reduced myelosuppression in mice treated with various chemotherapeutic agents. The mechanism of DDTC-mediated chemoprotection is believed to involve the induction and release of several cytokines, including interleukin-1 beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), and granulocyte colony-stimulating factor (G-CSF). In the present study the roles of IL-1beta and TNF-alpha in DDTC-mediated G-CSF induction were examined using human long-term bone marrow cultures (hLTBMCs). Administration of IL-1 receptor antagonist (IL-1ra) to DDTC-treated hLTBMCs obviated the G-CSF induction profile and blocked the resultant colony proliferation, indicating that IL-1beta mediates DDTC-induced G-CSF release and hematopoiesis. IL-1beta mRNA levels were increased threefold over control following DDTC treatment of hLTBMCs, implying that DDTC induces IL-1beta at the level of transcription. Conversely, studies involving inhibition of DDTC-induced TNF-alpha synthesis, with the inhibitor MNX 160, had no effect on DDTC-induced G-CSF release or colony proliferation. These findings taken together strongly suggest that IL-1beta mediates the chemoprotective effects of DDTC.
Kennedy
S M
SM
Department of Pharmacology and Physiology, University of Rochester, NY, USA.
Borch
R F
RF
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D002460:Cell Line; D004050:Ditiocarb / Q000494:pharmacology; D016179:Granulocyte Colony-Stimulating Factor / Q000096:biosynthesis*; D006410:Hematopoiesis / Q000187:drug effects*; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000494:pharmacology*; D051379:Mice; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors / Q000502:physiology; D012795:Sialoglycoproteins / Q000494:pharmacology
D000276:Adjuvants, Immunologic; C507763:IL1RN protein, human; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D017472:Receptors, Interleukin-1; D012795:Sialoglycoproteins; D016179:Granulocyte Colony-Stimulating Factor; D004050:Ditiocarb