Impaired Erythropoietin Epo Production

As shown by a number of investigators, patients with a variety of inflammatory conditions, including cancer or connective tissue disorders, have a blunted Epo response for the degree of anemia that is present (1). Thus, the typical logarithmic increase in plasma or urine Epo levels seen with increasing anemia is lost in patients with ACI (2).

An elegant series of experiments was carried out by Faquin et al. (3). They established cultures of the human hepatoma cell line, Hep3b. These cells have the useful property of upregulating Epo gene expression in response to hypoxia and secreting Epo into the medium (4). The results demonstrated that when inflammatory cytokines such as Interleukin-1 (IL-1) or tumor necrosis factor a (TNFa) were added to the cultures, Epo production in response to hypoxia was dramatically reduced (Fig. 4.1). The suppressive effect of the cytokines was dose-dependent and these investigators established a hierarchy of effects with IL-1P being more suppressive than IL-1 a which, in turn, was followed by TNFa and TGFp. Not only was Epo messenger RNA reduced in the presence of the inflammatory cytokines, but the amount of immunoreactive Epo secreted into the culture medium was similarly reduced.

Table 4.1. Conditions Associated with ACI

1. Acute and chronic infection (viral, bacterial, protozoal)

2. Autoimmune disease (e.g., rheumatoid arthritis)

3. Tissue injury (e.g., surgery, trauma, myocardial infarction, menses)

4. Neoplasms

5. Chronic renal failure

6. Aging

Fig. 4.1. Effect of IL-1 and TNF on erythropoietin gene expression (adapted from 3). This research was originally published in Blood. ┬ęthe American Society of Hematology

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