A highly enhanced thrombopoietic activity by monomethoxy polyethylene glycol-modified recombinant human interleukin-6.
Interleukin-6 (IL-6) is a novel cytokine with activities that can affect hematopoietic cells including those of the megakaryocytic lineage. We have examined the effects of monomethoxy polyethylene glycol-modified recombinant human interleukin-6 (Peg-IL-6) on thrombopoiesis in vivo. To compare the thrombopoietic activity between Peg-IL-6 and unmodified IL-6, each was administered subcutaneously to mice every 24 hours at various doses. A dose-response experiment showed that Peg-IL-6 and IL-6 increased platelet counts in a dose-dependent fashion at a plateau stimulation level of 0.5 micrograms/day and 10 micrograms/day, respectively. This dose of Peg-IL-6 and IL-6 induced the elevated platelet counts by approximately 140% to 160% and 50% to 60%, respectively. Peg-IL-6 treatment (0.5 micrograms/day) for x-ray (6.0 Gy) irradiated mice induced an increase in the rate of platelet recovery, and a higher dosage (5 micrograms/day) completely blocked the induction of thrombocytopenia in this model. In contrast, IL-6 (10 micrograms/day) could not protect the animals from platelet nadir but reduced the period of thrombocytopenia after x-ray irradiation. Furthermore, when administered to 5-fluorouracil-treated mice, 5 micrograms/day of Peg-IL-6 diminished the platelet nadir and increased platelet counts on individual days during the recovery phase. The potent thrombopoietic activity of Peg-IL-6 were due to prolongation of circulating IL-6 levels that were reverted from Peg-IL-6 in vivo. These findings indicate that reduction of total body clearance of IL-6 induces potent thrombopoiesis and that Peg-IL-6 may be a useful thrombopoietic agent.
Inoue
H
H
Pharmaceutical Research Laboratory, Kirin Brewery Co., Ltd., Maebashi, Japan.
Kadoya
T
T
Kabaya
K
K
Tachibana
K
K
Nishi
N
N
Sato
M
M
Ohsawa
M
M
Mikayama
T
T
Mori
K J
KJ
D000818:Animals; D001792:Blood Platelets / Q000502:physiology*; D003114:Colony-Forming Units Assay; D005472:Fluorouracil; D006410:Hematopoiesis; D015850:Interleukin-6 / Q000097:blood / Q000494:pharmacology*; D008297:Male; D008533:Megakaryocytes / Q000166:cytology; D051379:Mice; D008807:Mice, Inbred BALB C; D011092:Polyethylene Glycols / Q000494:pharmacology*; D011833:Radiation Injuries, Experimental; D011994:Recombinant Proteins; D013921:Thrombocytopenia / Q000097:blood / Q000139:chemically induced / Q000209:etiology
D015850:Interleukin-6; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; C028210:monomethoxypolyethylene glycol; D005472:Fluorouracil