Myelodysplasia and anemia of chronic disease in human tumor necrosis factor-alpha transgenic mice.
TNF-alpha is a pleitropic cytokine that expresses both pro- and anti-inflammatory activity and transgenic mice expressing human tumor necrosis factor-alpha (TNF-alpha) exhibit a progressive polyarthritis that models rheumatoid arthritis (RA). One of the common comorbidities of RA is anemia of chronic disease (ACD). The purpose of these experiments was to study the changes in the bone marrow and peripheral blood that accompany polyarthritis in TNF-alpha transgenic mice in an effort to better understand the pathogenesis of myelodysplasia and ACD. Polychromatic cytometry, hematology and serum cytokine analysis were used to study the pathogenesis of ACD in human TNF-alpha transgenic mice. Our hematological evaluation revealed a mild, compensated, microcytic hypochromic anemia, and monocytosis. In the bone marrow, we observed alterations in cell kinetics, decreased relative expression of transferrin receptor and increased apoptosis and cell death in several late precursor cell populations. Although significant levels of human TNF-alpha were found in the serum, neither change in serum murine erythropoietin nor any significant difference observed in serum levels of murine IL-beta, IL-5, IL-6, IL-10, IL-12(p70), IL-17, TNF-alpha, IFNgamma, GM-CSF, MIP-1alphaJE, MCP-5 was observed. Tg197 mice develop a compensated, microcytic, hypochromic anemia, and a functional iron deficiency by 9 weeks of age. Changes in peripheral blood are reflected in alterations in cell kinetics, transferrin receptor expression and markedly increased apoptosis and cell death in the bone marrow indicating that TNF-alpha may contribute to myelodysplasia in ACD. Moreover, since human TNF-alpha can interact only with murine TNFR1, our data suggest that TNFR1 may play an important role in the development of ACD.
Capocasale
Renold J
RJ
Discovery Research, Centocor, Research and Development, Inc., Radnor, Pennsylvania 19087, USA. RCapocas@CNTUS.JNJ.com
Makropoulos
Dorie A
DA
Achuthanandam
Ram
R
Stowell
Nicole
N
Quinn
John
J
Rafferty
Patricia A
PA
O'Brien
Joanne
J
Emmell
Eva
E
Bugelski
Peter J
PJ
D000747:Anemia, Hypochromic / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001168:Arthritis / Q000378:metabolism / Q000473:pathology*; D001853:Bone Marrow / Q000378:metabolism; D016923:Cell Death / Q000502:physiology; D002908:Chronic Disease; D016207:Cytokines / Q000097:blood*; D006801:Humans; D017746:Joint Capsule / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009190:Myelodysplastic Syndromes / Q000378:metabolism / Q000473:pathology*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000502:physiology*
D016207:Cytokines; D047888:Receptors, Tumor Necrosis Factor, Type I; C439524:TNF protein, human; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha