Cytokine Concentrations in Bone Marrow of Stable Sickle Cell Anemia Patients

Abstract

Inflammation plays a significant role in the clinical manifestations of sickle cell anemia. In studies of anemic patients with other clinical syndromes, measurement of the concentrations of cytokine mediators of inflammation in bone marrow aspirates has provided unique correlations with clinical and laboratory parameters. We determined concentrations of interleukin (IL)-1, IL-6, tumor necrosis factor (TNF), and placental growth factor (PlGF) in bone marrow aspirates from six homozygous sickle cell (SS) patients who were not acutely ill and who were not receiving hydroxyurea, erythropoietin, or chronic transfusion and compared them with specimens from seven healthy controls. We also measured concentrations of soluble transferrin receptor (sTfR) and of marrow erythroid colony-forming units (CFU-E) as markers of erythropoietic activity. sTfR concentration was significantly higher in SS patients (p = .024). CFU-E concentration was not significantly different between the two groups. Bone marrow concentrations of IL-6 and IL-1 did not differ between the study groups. TNF was undetectable in all specimens, plasma or marrow. Bone marrow PlGF concentrations were significantly higher in SS patients (p = .004). Since PlGF is a product of erythroid cells, the ratio of marrow PlGF to marrow sTfR was determined and found to be significantly greater in SS patients. This suggests that the observed difference in marrow PlGF concentrations does not reflect increased erythropoiesis but rather represents increased PlGF production per erythroid unit.

Granulocyte colony-stimulating factor (G-CSF) administration in individuals with sickle cell disease: time for a moratorium?

“…SCD has been described as a chronic inflammatory state, with elevated leukocyte counts, increased serum levels of C-reactive protein and cytokines [8, 9], and a propensity for erythrocyte and platelet activation [10], all processes that might be exacerbated by G-CSF usage. A number of prospective clinical trials have demonstrated a correlation between leukocytosis and sickle-related complications including increased mortality [11–13].…”

Placental growth factor attenuates suppression of erythroid colony formation by interferon

“…It is a cytokine that appears to distinguish SS patients from healthy controls(9); it is produced by erythroid cells(9); and it is measurable in marrow aspirate plasma at higher concentrations than are seen in concurrent serum or plasma samples(11). The experiments in this report demonstrate that CFU-E colony formation from SS patients is relatively resistant to inhibition by rhγIFN, and that the addition of rhPlGF to cell cultures can confer this resistance phenotype on CFU-E from the marrow of healthy control subjects.…”

“…Other investigators found similar results, but only during acute painful crises(10). In studies of the contribution of inflammatory cytokines to the regulation of erythropoiesis in homozygous sickle cell (SS) patients, we measured concentrations of PlGF, interleukin (IL)-1, IL-6, tumor necrosis factor (TNF) and γ interferon (IFN) in marrow aspirates from steady-state, low severity SS patients and healthy volunteer control subjects(11). Marrow aspirate PlGF concentrations were significantly higher in SS patients than in controls; there were no differences in the other cytokines measured.…”

“…The marrow aspirate plasma concentrations were higher than the concentrations detectable in concurrent serum or plasma specimens from SS patients. When the PlGF concentrations were normalized to marrow erythroid progenitor content, the difference between SS patients and controls persisted, suggesting that the increased marrow PlGF concentrations did not derive from increased erythroid activity, but rather represented an increase per erythropoietic unit(11). In this study, we evaluate the possibility that PlGF interferes with suppression of erythropoiesis by inflammatory mediators.…”