IL-12 facilitates both the recovery of endogenous hematopoiesis and the engraftment of stem cells after ionizing radiation.
OBJECTIVE
Severe myelosuppression is a common side effect of radiotherapy or chemotherapy. Methods have been developed to protect patients by stimulating white blood cell or red blood cell recovery/production using growth factors such as G-CSF or EPO. However, there is no available means to stimulate the full-lineage blood cell recovery from severe myelosuppression. In this study, we used lethally or sublethally irradiated animal models to evaluate the hematopoiesis stimulating effect of IL-12.


METHODS
IL-12-treated lethally or sublethally irradiated animals were examined for the survival/lifespan, the function assays (bone marrow transplantation, CFU-S(12), CFC) of bone marrow cell subsets, and apoptosis assay.


RESULTS
Using a low dose of IL-12 (10 times lower than previously reported dose), 91.4% of lethally irradiated animals survived long term without adverse effects on the gastrointestinal (GI) system. The reconstituted hematopoietic system was derived from long-term reconstituting hematopoietic stem cells (LTR HSC), which reconstituted hematopoiesis both endogenously after lethal radiation and in secondary recipients by bone marrow transplantation (BMT). IL-12 significantly attenuated the decline of blood cell counts in sublethally irradiated animals. The IL-12-stimulated hematopoiesis recovery resulted in a full-lineage blood cell production, including white and red blood cells, and platelets. There was no detectable expression of IL-12 receptor on LTR HSC. In IL-12-treated animals, the number of Sca-1(+) cells was significantly higher than in animals without IL-12 treatment.


CONCLUSIONS
In this study, we showed a low dose of IL-12 has hematopoietic-protecting effects, which can attenuate severe myelosuppresion caused by lethal or sublethal irradiation. This study, together with previous studies showing IL-12 is also an anti-tumor and anti-angiogenic agent, suggest IL-12 may have clinical significance in cancer treatment and BMT.
Chen
Tingchao
T
Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Burke
Kathleen A
KA
Zhan
Yuxia
Y
Wang
Xingchao
X
Shibata
Darryl
D
Zhao
Yi
Y
D000818:Animals; D001773:Blood Cells / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D005260:Female; D005720:Gamma Rays; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D006085:Graft Survival / Q000187:drug effects* / Q000528:radiation effects; D006410:Hematopoiesis / Q000187:drug effects* / Q000528:radiation effects; D018380:Hematopoietic Stem Cell Transplantation; D018664:Interleukin-12 / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011837:Radiation-Protective Agents / Q000494:pharmacology; D020127:Recovery of Function / Q000187:drug effects*; D013234:Stem Cells / Q000187:drug effects* / Q000528:radiation effects; D015996:Survival Rate; D013997:Time Factors; D014916:Whole-Body Irradiation
D011837:Radiation-Protective Agents; D018664:Interleukin-12