NEGATIVE REGULATORS OF INVIVO ERYTHROPOIESIS - INTERACTION OF IL-1-ALPHA AND TNF-ALPHA AND THE LACK OF A STRICT REQUIREMENT FOR T-CELLS OR NK CELLS FOR THEIR ACTIVITY

The macrophage-derived cytokines interleukin 1-alpha (IL-1-alpha) and tumor necrosis factor-alpha (TNF-alpha) have significant effects on hematopoiesis in vitro and in vivo. Studies in our laboratory have demonstrated that, in vivo, IL-1-alpha and TNF-alpha suppress late stage erythropoiesis while stimulating the macrophage-granulocyte lineage. In the present studies, we have examined the mechanisms of these effects. Normal mice were treated with a single dose of either recombinant murine IL-1-alpha or TNF-alpha (1.25 x 10(6) or 10(5) U/mouse i.p., respectively) with or without pretreatment of the animals with monoclonal anti-murine TNF-alpha antibody at a dose that has been shown to be capable of abrogating endogenous TNF activity induced by lipopolysaccharide (LPS). After 5 days, effects on late-stage erythropoiesis and macrophage formation were measured by determining the number of their progenitors, erythroid colony-forming units (CFU-E) and macrophage colony-forming units (CFU-M), in the spleen. Anti-TNF-alpha antibody treatment significantly abrogated CFU-E suppression by IL-1-alpha but had no effect on the IL-1-alpha-induced stimulation of CFU-M. IL-1-alpha and TNF-alpha suppressed CFU-E in vivo and stimulated CFU-M in the spleens of T-cell-and natural killer (NK)-cell-deficient mice. Neither cytokine suppressed CFU-E colony formation in vitro. These results demonstrate that IL-1-alpha-induced suppression of CFU-E is mediated through induction of TNF-alpha, IL-1-alpha stimulation of CFU-M was independent of TNF-alpha, and the in vivo hematopoietic effects of these cytokines do not strictly require intact T- and NK-cell function for activity.