Tumor Necrosis Factor α and the Anemia of Chronic Disease: Effects of Chronic Exposure to TNF on Erythropoiesis in Vivo

Abstract

The anemia of chronic disease is associated with conditions in which macrophage activation occurs. Activated marrow macrophages suppress erythropoiesis in vitro, and produce tumor necrosis factor (TNF). Therefore we tested the effects of chronic in vivo exposure to TNF to determine if it were a candidate for a mediator of the anemia of chronic disease. Nude mice were inoculated with CHO cells expressing the human TNF gene, or with control cells containing the transfection vector alone. The TNF mice promptly became reticulocytopenic, and after 3 weeks their corrected reticulocytes were 2.6±.7% compared to 7.3±4% in control mice. The hematocrit at 3 weeks was 28.4±1.7% in TNF mice compared to 46±8% in control mice. This anemia was also associated with low serum iron and normal iron stores and increased erythropoietin levels. The TNF mice showed an absolute monocytosis with twice the number of circulating monocytes as control mice. The TNF mice also became mildly thrombocytopenic. Marrow CFU-E and BFU-E were profoundly decreased (1.2±2xl0* vs 8.6±2xl04 CFU-E per femur, and 6.5±lxl0² vs 8.5±.2xl0⁴ BFU-E per femur). Splenic CFU-E and BFU-E were similarly depressed. In contrast, marrow CFU-GM and CFU-GEMM were not affected. Administration of recombinant human erythropoietin to these mice failed to reverse the suppressed erythropoiesis in mice bearing TNF producing tumors. These data demonstrated that TNF preferentially inhibits erythropoiesis in vivo, and may be important in the pathogenesis of the anemia of chronic disease.