Cachectin/tumor necrosis factor-alpha alters red blood cell kinetics and induces anemia in vivo.
Chronic inflammatory diseases are often associated with decreased red blood cell (RBC) mass. The cytokines cachectin/tumor necrosis factor-alpha (TNF) and interleukin 1 (IL 1) are produced by monocytes/macrophages in response to many inflammatory stimuli and have been implicated in the anemia of chronic disease. This study was undertaken to evaluate the mechanisms by which cachectin/TNF, IL 1, or endotoxin induce anemia. Hematologic parameters and RBC kinetics were quantitated in rats given chronic sublethal quantities of either recombinant human cachectin/TNF, recombinant human IL 1 alpha, or Salmonella endotoxin for 7 days. Cachectin/TNF or endotoxin treatment resulted in a 25 or 31% decrease, respectively, in total RBC mass, whereas RBC mass was unchanged by IL 1 administration. Anemia associated with either chronic cachectin or endotoxin administration was characterized by normal mean corpuscular volume, mean corpuscular hemoglobin content, and reticulocyte numbers. [59Fe]RBC survival was significantly shortened in animals given cachectin, IL 1 or endotoxin, but the magnitude of the response was greatest in cachectin/TNF-or endotoxin-treated rats. Although cachectin/TNF-IL 1-, or endotoxin treatment resulted in similar hypoferremia and shortened plasma iron half-life, endotoxin or cachectin/TNF treatment (but not IL 1) significantly reduced the incorporation of plasma 59Fe into newly synthesized RBCs. We conclude that chronic cachectin/TNF administration produces anemia by decreasing RBC synthesis and reducing the life span of circulating RBCs. An endogenous cachectin/TNF response during inflammatory disease may contribute to an associated anemic state, whereas the modestly reduced red cell life span induced by IL 1 does not lead to a net reduction in RBC mass, presumably owing to a preserved RBC synthetic rate.
Department of Surgery, New York Hospital, Cornell University Medical Center, New York 10021.
L L
LL
Moldawer
M A
MA
Marano
H
H
Wei
Y
Y
Fong
M L
ML
Silen
G
G
Kuo
K R
KR
Manogue
H
H
Vlassara
H
H
Cohen
A
A
Cerami
D000740:Anemia / Q000139:chemically induced*; D000818:Animals; D001798:Blood Proteins / Q000494:pharmacology; D002298:Cardenolides; D004077:Digoxin; D004905:Erythrocyte Aging; D004909:Erythrocyte Indices; D004912:Erythrocytes / Q000502:physiology*; D006207:Half-Life; D006400:Hematocrit; D006454:Hemoglobins / Q000378:metabolism; D007375:Interleukin-1 / Q000494:pharmacology; D007501:Iron / Q000097:blood; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011994:Recombinant Proteins / Q000494:pharmacology; D012475:Salmonella; D012503:Saponins; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D001798:Blood Proteins; D002298:Cardenolides; D006454:Hemoglobins; D007375:Interleukin-1; D011994:Recombinant Proteins; D012503:Saponins; D014409:Tumor Necrosis Factor-alpha; C034504:digoxin-like factors; D004077:Digoxin; D007501:Iron