Biology Reference
In-Depth Information
Impaired marrow response
The inability of the marrow to compensate for the modest reduction in red cell
life-span seen in ACD results from the combination of an impaired EPO
response to anemia and from impairment of the ability of the erythroid pro-
genitors to respond to EPO. An inverse relationship exists between serum or
plasma EPO concentrations and hemoglobin. As the hemoglobin concentration
decreases, the EPO concentration increases [38]. A similar inverse relationship
between hemoglobin and EPO was observed in anemic patients with rheuma-
toid arthritis [39]; however, for any given anemic individual with rheumatoid
arthritis, the EPO concentration was lower than that found in equally anemic
individuals with iron deficiency. This result indicated that the EPO response to
anemia was blunted in patients with rheumatoid arthritis. Similar results have
been reported in anemic patients with systemic lupus erythematosus [40]. This
impaired EPO response appears to be a cytokine-mediated effect. IL-1, TNF-
β
,
and transforming growth factor (TGF)-
inhibit production of EPO
in vitro
by
hepatoma cell lines exposed to hypoxia or by isolated perfused rat kidneys [41,
42].
Although the EPO concentrations of patients with ACD are not as high as
those found in equally anemic iron-deficient individuals, these concentrations
are still higher than those found in normal individuals who are not anemic.
This finding indicates that EPO concentrations are not the sole determinant of
impaired erythropoiesis in ACD. Clinical studies in various syndromes have
supported this concept [31, 43]. TNF, IL-1, and the IFN have been reported to
inhibit erythroid colony formation and erythropoiesis
in vivo
and
in vitro
[25,
44-53].
The mechanisms by each of these cytokines act appears to differ widely.
Erythroid colony-forming cells (CFU-E) appear to be relatively resistant to
direct inhibition by TNF, IL-1, and IFN-
β
. These cytokines appear to act pri-
γ
γ
marily by inducing other cytokines that are directly inhibitory to CFU-E, such
as IFN-
[54-57].
Considerable attention has been devoted to the elucidation of the cellular
mechanisms by which IFN-
or IFN-
γ
β
and IFN-
γ
exert their effects on CFU-E forma-
β
tion. rHuIFN-
induces apoptosis in CFU-E. This process appears to require
Fas
[58]. Ceramide, a product of sphingomyelin hydrolysis, is a known medi-
ator of apoptotic effects of TNF, IL-1, and IFN-
γ
, and is frequently implicated
γ
γ
in
Fas
-mediated events. Endogenous ceramide produced by exposure to bac-
terial sphingomyelinase (0.2 to 2.0 U/mL) and exogenous cell-permeable
ceramide (C2-ceramide; at concentrations <10 mM) significantly inhibited
bone marrow CFU-E formation. This effect was reversed by the ceramide
antagonist sphingosine-1-phosphate. Inhibition of CFU-E by rHuIFN-
,but
γ
not rHuIFN-
, was also reversed by sphingosine-1-phosphate. In addition,
recombinant human (rHu)EPO 10 U/mL reversed CFU-E inhibition by C2-
ceramide 10 mM. Exposure of marrow cells to rHuIFN-
β
led to a 57% increase
in ceramide content. These findings strongly suggest that ceramide is involved
γ
