Chronic exposure to tumor necrosis factor in vivo preferentially inhibits erythropoiesis in nude mice.

The anemia of chronic disease (ACD) 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 was a candidate for a mediator of ACD. Nude mice were inoculated with Chinese hamster ovary (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% +/- 0.7% as compared with 7.3% +/- 4% in control mice. The hematocrit at 3 weeks was 28.4% +/- 1.7% in TNF mice as compared with 46% +/- 0.8% in control mice. This anemia was also associated with low serum iron and normal iron stores and increased erythropoietin (Epo) levels. The TNF mice showed an absolute monocytosis with twice the number of circulating monocytes as control mice and had M-colony-stimulating factor (CSF) activity in their serum. The TNF mice also became mildly thrombocytopenic. Marrow CFU-E and BFU-E were profoundly decreased (1.2 +/- 0.2 x 10(3) v 8.6 +/- 0.2 x 10(4) CFU-E per femur, and 6.5 +/- 1 x 10(2) v 8.5 +/- 0.2 x 10(4) BFU-E per femur). Splenic CFU-E and BFU-E were similarly depressed. In contrast, marrow CFU-GM and CFU-GEMM were not affected. The residual BFU-E in TNF mice were relatively resistant to TNF as compared with control mice. These data demonstrate that TNF preferentially inhibits erythropoiesis in vivo and may be important in the pathogenesis of ACD.