Interferon-gamma induced nitric oxide-mediated apoptosis of anemia of chronic disease in rheumatoid arthritis

Abstract

Proinflammatory cytokines play a role in the pathogenesis of anemia of chronic disease (ACD), which is a common cause of anemia in rheumatoid arthritis (RA). Anemia in RA is associated with increased apoptosis of erythroid cells. However, there is unclear information on the mechanism of ACD in the disease. The purpose of this study is to investigate the role of cytokines on nitric oxide-mediated apoptosis in erythroid progenitor cells of ACD in RA patients. Erythroid progenitor cells from healthy subjects and RA patients with ACD were treated with cytokines like interleukin-1β, tumor necrosis factor-α, and interferon-γ at concentrations of 2, 20, and 40 ng/ml for 14 days. Cell viability and cell apoptosis were analyzed by trypan blue staining and flow cytometry, respectively. The results showed that the highest effect of cytokines on reduction cell viability and induction cell apoptosis was found in 20 ng/ml IFN-γ-treated cells of RA patients. In addition, IFN-γ showed significantly increased nitric oxide production and iNOS mRNA expression, which was measured by Griess assay and real-time PCR, respectively. The percentage of cell apoptosis and NO production was reduced after an inducible nitric oxide synthase inhibitor, SMT, treatment. In conclusion, IFN-γ could induce nitric oxide production-mediated apoptosis process, which might be involved in the pathogenesis of ACD in RA patients.

Anaemia of Chronic Disease: An In-Depth Review

“…Activation of this pathway leads to production of intracellular factors which enhance apoptosis by regulating transcription and eventual myelosuppression. IFN-γ stimulates ferritin transcription on the one hand and inhibits transferrin receptor (TfR) mRNA expression via an iron-regulatory element-protein-independent process [ 20 , 21 , 22 ]. It also increases expression of DMT-1, which is involved in the active transport of ferrous molecules from the lumen to the duodenal endothelial cell cytoplasm [ 21 ].…”

“…Hepcidin inhibits the export of iron from the enterocytes, hepatocytes, and marrow macrophages [ 10 , 32 ], thereby creating a hypoferraemic environment, and thus denies the invading microbes as well as the erythroid cells their much-needed iron. IFN-γ induces apoptosis in erythroid precursors by increasing nitric oxide production and inducible nitric oxide synthase mRNA production [ 22 ]. IFN-γ and to a lesser extent IFN-α and -β have been observed to induce apoptosis of the erythroid burst-forming and colony-forming units.…”

“…Inversely, the production of free oxygen radicals in inflammation causes release of pro-inflammatory cytokines including hepcidin. Other pro-inflammatory cytokines like IFN-γ cause increased expression of inducible nitric oxide mRNA and the subsequent production of nitric oxide [ 22 ]. This in conjunction with the production of superoxide molecules in inflammation may cause reversal of the effects of hypoxia on hepcidin production.…”

Anemia in Elderly: A Review

“…22 It stimulates ferritin transcription and also inhibits transferrin receptor (TfR) mRNA expression which ultimately results in decrease intestinal transport of iron from gut lumen to blood. [23][24][25][26] Cytokines also exert a direct toxic effect on progenitor cells by inducing the formation of free radicals by neighboring macrophage-like cells. 13 In ACD, erythropoietin production is inhibited by combined effect of raised hepcidin and direct inhibition of the EPO promoter gene through cytokine-induced toxic radicals.…”

Extraskeletal Manifestations in Rheumatoid Arthritis - Clinical Cases

“…IFN-γ is a key modulator of macrophage iron status and immune functions [13]. In vitro studies show that IFN-γ could induce nitric oxide production-mediated apoptosis process, which might be in-volved in the pathogenesis of anemia in RA patients [19]. There is evidence suggesting that increased local IFN-γ production in bone marrow may be implicated in the pathogenesis of anemia seen in up to 50% of patients with RA [20].…”