Interleukin 11 significantly increases plasma von Willebrand factor and factor VIII in wild type and von Willebrand disease mouse models.
Interleukin (IL)-11 is a cytokine with thrombopoietic activity that has been shown to increase plasma von Willebrand factor (vWf) in preliminary clinical studies. This led to further evaluation of the effect of recombinant human (rh)IL-11 on vWf and factor VIII (FVIII) secretion. In vitro, rhIL-11 did not increase vWf production by cultured endothelial cells, which suggests an indirect mechanism. Also, in vivo, plasma vWf was not elevated in mice shortly after a single intravenous (IV) bolus injection of 250 or 1000 microg/kg rhIL-11. The effect of continuous exposure to rhIL-11 was accessed by treating wild type mice for 7 consecutive days with subcutaneous 250 microg/kg/d rhIL-11. Platelet counts increased by 25% and 40% after 4 and 7 days, respectively. Plasma vWf and FVIII levels increased 2-fold after 4 and 7 days. Surprisingly, no effect of rhIL-11 on vWf or FVIII messenger RNA was observed, which suggests that the regulation by rhIL-11 occurs after transcription. No increase in soluble P-selectin was observed after rhIL-11 treatment, indicating that platelet activation is not the source of elevated vWf. Similarly to wild type mice, vWf heterozygous mice responded to rhIL-11 treatment by a significant increase in platelet counts and vWf and FVIII levels. Importantly, in vWf-deficient mice, rhIL-11 also induced a significant increase in FVIII independent of vWf and was able to reduce skin bleeding time. These results suggest that a clinical evaluation of the effects of rhIL-11-induced vWf/FVIII elevation in maintaining hemostasis in mild hemophilia A or von Willebrand disease would be worthwhile.
Denis
C V
CV
The Center for Blood Research and the Department of Pathology, Harvard Medical School, Boston, MA 02115-6399, USA.
Kwack
K
K
Saffaripour
S
S
Maganti
S
S
André
P
P
Schaub
R G
RG
Wagner
D D
DD
D000818:Animals; D001760:Bleeding Time; D018929:Cell Culture Techniques; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005169:Factor VIII / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D006579:Heterozygote; D006801:Humans; D017370:Interleukin-11 / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D019007:P-Selectin / Q000097:blood / Q000187:drug effects; D010976:Platelet Count; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D013997:Time Factors; D014470:Umbilical Cord / Q000166:cytology; D014842:von Willebrand Diseases / Q000097:blood*; D014841:von Willebrand Factor / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism
D017370:Interleukin-11; D019007:P-Selectin; D011994:Recombinant Proteins; D014841:von Willebrand Factor; D005169:Factor VIII