Interleukin 1 receptor antagonist inhibits normal hematopoiesis and reduces lethality and bone marrow toxicity of 5-fluouracil in mouse.
5-Fluouracil (5-Fu) targeting of cycling hematopoietic cells results in bone marrow (BM) suppression. Interleukin 1 receptor antagonist (IL-1Ra) is a cytokine that competitively blocks the binding of interleukin 1 (IL-1) to its receptor. Unlike the supporting role of IL-1 less is known for the role of IL-1Ra in hematopoiesis. Here, we demonstrate that IL-1Ra expression in BM cells and in circulation was elevated temporarily during 5-Fu-induced myelosuppression. Exogenous IL-1Ra administered to normal mice reversibly inhibited cycling status of BM cells, and reduced the numbers of BM cells including colony-forming progenitor cells, white blood cells (WBCs), and platelets in a dosage-dependent and time-dependent fashion. Due perhaps to its reversible suppression of the cell cycle progression of BM cells, pretreatment of normal mice with exogenous IL-1Ra reduced the acute lethal toxicity and BM suppression of 5-Fu, and accelerated the recoveries of BM cells and platelets following 5-Fu treatment. Pretreatment with IL-1Ra offers a new promising strategy to alleviate the BM toxicity of chemotherapy in clinical settings.
Zhang
Jing
J
Laboratory of Regeneration, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, PR China.
Xiang
Di
D
Zhu
Shunying
S
Mao
Wenwei
W
Lu
Huili
H
Wu
Mingyuan
M
Wang
Qun
Q
Yu
Yan
Y
Herbst
Kenneth D
KD
Han
Wei
W
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000633:toxicity*; D001772:Blood Cell Count; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects*; D001855:Bone Marrow Diseases / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D045744:Cell Line, Tumor; D005260:Female; D005472:Fluorouracil / Q000633:toxicity*; D006410:Hematopoiesis / Q000187:drug effects*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000096:biosynthesis* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011994:Recombinant Proteins / Q000494:pharmacology
D000964:Antimetabolites, Antineoplastic; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D011994:Recombinant Proteins; D005472:Fluorouracil