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* Division of Experimental Hematology, Cincinnati Children’s Research Foundation and Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229;
Clinical Transplantation Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109;
Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan; and
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229
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-
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by a Leukemia Research Foundation Grant, a Trustee Grant, and National Institutes of Health Grants R01 CA109641 and R01 HL076712.
2 Address correspondence and reprint requests to Dr. Qishen Pang, Division of Experimental Hematology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229. E-mail address: qishen.pang{at}cchmc.org
3 Abbreviations used in this paper: FA, Fanconi anemia; 7-AAD, 7-aminoactinomycin D; HSC, hemopoietic stem cell; LSK, lineage-negative, Sca-1-positive, c-kit-positive; MDS, myelodysplasia; MPO, myeloperoxidase; NAC, N-acetyl-L-cysteine; ROS, reactive oxygen species; SCF, stem cell factor; WT, wild type.
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