Accumulating evidence implicates innate immune activation in the pathobiology of
myelodysplastic syndromes. A key myeloid-related inflammatory
protein, S100A9, serves as a
Toll-like receptor ligand regulating
tumor necrosis factor-α and interleukin-1β production. The role of
myelodysplastic syndrome-related inflammatory
proteins in endogenous
erythropoietin regulation and response to erythroid-stimulating agents or
lenalidomide has not been investigated. The HepG2
hepatoma cell line was used to investigate in vitro
erythropoietin elaboration. Serum samples collected from 311 patients with
myelodysplastic syndrome were investigated (125 prior to treatment with erythroid-stimulating agents and 186 prior to
lenalidomide therapy). Serum concentrations of S100A9, S100A8,
tumor necrosis factor-α, interleukin-1β and
erythropoietin were analyzed by
enzyme-linked
immunosorbent assay. Using
erythropoietin-producing HepG2 cells, we show that S100A9,
tumor necrosis factor-α and interleukin-1β suppress transcription and cellular elaboration of
erythropoietin. Pre-incubation with
lenalidomide significantly diminished suppression of
erythropoietin production by S100A9 or
tumor necrosis factor-α. Moreover, in peripheral blood mononuclear cells from patients with
myelodysplastic syndromes,
lenalidomide significantly reduced steady-state S100A9 generation (P=0.01) and
lipopolysaccharide-induced
tumor necrosis factor-α elaboration (P=0.002).
Enzyme-linked
immunosorbent assays of serum from 316 patients with non-del(5q)
myelodysplastic syndromes demonstrated a significant inverse correlation between
tumor necrosis factor-α and
erythropoietin concentrations (P=0.006), and between S100A9 and
erythropoietin (P=0.01). Moreover, baseline serum
tumor necrosis factor-α concentration was significantly higher in responders to erythroid-stimulating agents (P=0.03), whereas
lenalidomide responders had significantly lower
tumor necrosis factor-α and higher S100A9 serum concentrations (P=0.03). These findings suggest that S100A9 and its nuclear factor-κB transcriptional target,
tumor necrosis factor-α, directly suppress
erythropoietin elaboration in
myelodysplastic syndromes. These
cytokines may serve as rational
biomarkers of response to
lenalidomide and erythroid-stimulating agent treatments. Therapeutic strategies that either neutralize or suppress S100A9 may improve erythropoiesis in patients with
myelodysplastic syndromes.