Bifunctional effect of the inflammatory cytokine tumor necrosis factor α on megakaryopoiesis and platelet production

Background and Objectives: Platelets are affected by many factors, such as infectious or aseptic inflammation, and different inflammatory states may induce either thrombocytopenia or thrombocytosis. Tumor necrosis factor alpha (TNF alpha) is an important inflammatory cytokine that has been shown to affect the activity of hematopoietic stem cells. However, its role in megakaryocyte (MK) development and platelet production remains largely unknown. This study aimed to investigate the effects of TNF alpha on MK and platelet generation. Methods and Results: The ex vivo study with human CD34(+) cells demonstrated that TNF alpha differentially modulated commitment toward the MK lineage. Specifically, a low concentration of 0.5 ng/ml TNF alpha promoted MK maturation, proplatelet formation, and platelet production, whereas a high concentration of 10 ng/ml or more TNF alpha exhibited a substantial inhibitory effect on MK and platelet production. The distinct effect of TNF alpha on MKs was mainly dependent on TNF alpha receptor 1. TNF alpha differentially regulated the MAPK-ERK1/2 signaling pathway and the cytoskeletal proteins cofilin and MLC2. The in vivo study with Balb/c mice indicated that low-dose or high-dose TNF alpha administration differentially affected short-term platelet recovery after bone marrow transplantation. Conclusions: Our study revealed distinct roles for TNF alpha in megakaryopoiesis and thrombopoiesis and may provide new insights regarding the treatment for platelet disorders.