Mechanisms of erythroid suppression in the anemia of chronic disease.
The mechanism underlying the hypoproliferative anemia in patients with chronic diseases has not been clearly defined. We have examined the effects of marrow macrophages from anemic patients with chronic diseases and normals to determine if they suppress erythroid progenitors in vitro. We found that marrow macrophages from patients with the anemia of chronic disease (ACD) significantly suppressed erythroid progenitor cell growth, whereas marrow macrophages from normals did not. Since ACD is seen in conditions that activate macrophages, we then determined if activated macrophages could suppress erythroid progenitor cell growth. Peritoneal macrophages activated by chronic Cryptococcus neoformans infection significantly suppressed erythroid progenitor cell growth, although resting macrophages did not. We then examined the effects of a product of activated macrophages, tumor necrosis factor (TNF), for its effects on CFU-E and BFU-E. TNF significantly suppressed CFU-E and BFU-E growth in concentrations as low as 10(-11)-10(-12) M. Preincubation of marrow samples with TNF for as little as 15 minutes was sufficient to suppress CFU-E and BFU-E growth. Addition of TNF, after the onset of culture could only suppress CFU-E and BFU-E if added within the first 48 hours. TNF (10(-10)-10(-11) M) also inhibited the growth of hematopoietic cell lines K562, HL60, and HEL cells. These cell lines expressed low numbers of high affinity TNF receptors, with 80%-90% of the cells expressing TNF receptors.
Roodman
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Research Service, Audie Murphy VA Hospital, San Antonio, TX 78284.
D000740:Anemia / Q000209:etiology* / Q000503:physiopathology; D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D001854:Bone Marrow Cells; D002478:Cells, Cultured; D002908:Chronic Disease / Q000150:complications* / Q000503:physiopathology; D004920:Erythropoiesis; D005260:Female; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D008262:Macrophage Activation; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D011956:Receptors, Cell Surface / Q000032:analysis; D018124:Receptors, Tumor Necrosis Factor; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology; D014410:Tumor Stem Cell Assay
D011956:Receptors, Cell Surface; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha