Hematopoietic cells from gadd45a-deficient and gadd45b-deficient mice exhibit impaired stress responses to acute stimulation with cytokines, myeloablation and inflammation.
The gadd45 family of gene(s) is rapidly induced by genotoxic stress or by differentiation-inducing cytokines. Using bone marrow (BM) from gadd45a-/-, gadd45b-/- and wild-type (wt) mice, we investigated their role in stress responses of myeloid cells to acute stimulation with differentiating cytokines, myelotoxic agents and inflammatory substances. Bone marrow cells from gadd45a-/- and gadd45b-/- mice displayed compromised myeloid differentiation and higher apoptosis in vitro, following acute stimulation with a variety of differentiating cytokines. Intriguingly, gadd45a-/- and gadd45b-/- colony forming units granulocyte/macrophage progenitors displayed prolonged proliferation capacity compared to wt controls upon re-plating in methylcellulose supplemented with interleukin-3. The recovery of the BM myeloid compartment following 5-Fluorouracil-induced myelo-ablation was much slower in gadd45a-/- and gadd45b-/- mice compared to wt controls. Furthermore, the response of myeloid cells to inflammatory stress, inflicted via intraperitoneal administration of sodium caseinate was impaired in gadd45a-/- and gadd45b-/- mice compared to age-matched wt mice, as indicated by lower percentage of Gr-1-positive cells in the BM and lower number of myeloid cells in peritoneal exudates. Overall, these data indicate that both gadd45a and gadd45b play a role in modulating physiological stress responses of myeloid cells to acute stimulation with differentiating cytokines, myelo-ablation and inflammation. These findings should aid in understanding the response of normal and malignant hematopoietic cells to physiological and chemical stressors including anticancer agents.
Gupta
S K
SK
Department of Biochemistry, Fels Institute for Cancer Research & Molecular Biology, Temple University School of Medicine, Philadelphia, PA 19104, USA.
Gupta
M
M
Hoffman
B
B
Liebermann
D A
DA
D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000502:physiology*; D017209:Apoptosis; D015152:Blotting, Northern; D001854:Bone Marrow Cells / Q000166:cytology; D002364:Caseins / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000494:pharmacology*; D005260:Female; D005269:Femur / Q000166:cytology; D005472:Fluorouracil / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D007249:Inflammation / Q000503:physiopathology*; D051379:Mice; D019653:Myeloablative Agonists / Q000494:pharmacology*; D022423:Myeloid Cells / Q000166:cytology / Q000502:physiology*; D038042:Myelopoiesis; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D000097642:GADD45 Proteins
D000943:Antigens, Differentiation; D002364:Caseins; D018797:Cell Cycle Proteins; D016207:Cytokines; D005472:Fluorouracil; D019653:Myeloablative Agonists; D009687:Nuclear Proteins; C499072:Gadd45a protein, mouse; D000097642:GADD45 Proteins; C490125:Gadd45b protein, mouse