Inflammatory reactive oxygen species-mediated hemopoietic suppression in Fancc-deficient mice.
Patients with the genomic instability syndrome Fanconi anemia (FA) commonly develop progressive bone marrow (BM) failure and have a high risk of cancer. Certain manifestations of the disease suggest that the FA immune system is dysfunctional and may contribute to the pathogenesis of both BM failure and malignancies. In this study, we have investigated inflammation and innate immunity in FA hemopoietic cells using mice deficient in Fanconi complementation group C gene (Fancc). We demonstrate that Fancc-deficient mice exhibit enhanced inflammatory response and are hypersensitive to LPS-induced septic shock as a result of hemopoietic suppression. This exacerbated inflammatory phenotype is intrinsic to the hemopoietic system and can be corrected by the re-expression of a wild-type FANCC gene, suggesting a potential role of the FANCC protein in innate immunity. LPS-mediated hemopoietic suppression requires two major inflammatory agents, TNF-alpha and reactive oxygen species. In addition, LPS-induced excessive accumulation of reactive oxygen species in Fancc(-/-) BM cells overactivates the stress kinase p38 and requires prolonged activation of the JNK. Our data implicate a role of inflammation in pathogenesis of FA and BM failure diseases in general.
Sejas
Daniel P
DP
Division of Experimental Hematology, Cincinnati Children's Research Foundation and Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Rani
Reena
R
Qiu
Yuhui
Y
Zhang
Xiaoling
X
Fagerlie
Sara R
SR
Nakano
Hiroyasu
H
Williams
David A
DA
Pang
Qishen
Q
D000818:Animals; D001855:Bone Marrow Diseases / Q000209:etiology*; D005199:Fanconi Anemia / Q000209:etiology*; D052218:Fanconi Anemia Complementation Group C Protein / Q000172:deficiency* / Q000502:physiology; D006410:Hematopoiesis / Q000187:drug effects; D007249:Inflammation / Q000150:complications*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C497652:Fancc protein, mouse; D052218:Fanconi Anemia Complementation Group C Protein; D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases