Failure of interferon-gamma and tumor necrosis factor in mediating anemia of chronic disease in a mouse model of protracted septic peritonitis.

Interferon-gamma (IFN-gamma) is considered one of the main inflammatory cytokines contributing to the generation of anemia of chronic disease (ACD). In this study, we used a previously described murine model for ACD based on sublethal cecal ligation and puncture (CLP) with ensuing protracted peritonitis. Within 2 weeks after CLP, a moderate normochromic anemia with low serum iron concentration and preserved iron stores develops, which is consistent with ACD. In order to determine whether IFN-gamma contributes to the development of ACD in vivo, we neutralized IFN-gamma after CLP shortly before and during the phase of most severe bone marrow depression in order to prevent anemia. Additionally, we studied IFN-gamma receptor-deficient mice that underwent CLP. Two weeks after CLP, we determined the red blood cell count, hemoglobin concentration, hematocrit, serum iron concentration, and iron stores in spleens of wild-type mice, IFN-gamma receptor-deficient mice, and mice after neutralization of IFN-gamma. Neutralization of IFN-gamma after CLP could not prevent mice from becoming anemic. Accordingly, IFN-gamma receptor-deficient mice developed anemia to the same extent as wild-type mice. Serum iron concentration was lowered both in IFN-gamma receptor-deficient and wild-type mice. Iron stores in untreated IFN-gamma receptor-deficient mice were elevated compared to untreated wild-type mice. After CLP both IFN-gamma receptor-deficient and wild-type mice had equally overloaded iron stores. Additional neutralization of TNF in IFN-gamma receptor-deficient mice also did not attenuate CLP-induced anemia. Our results clearly demonstrate that neither IFN-gamma alone nor in combination with TNF is a mediator of ACD in our model with transient anemia induced by protracted septic peritonitis.