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TNF-alpha is a pleiotropic cytokine with stimulatory as well as inhibitory effects on hematopoiesis. We have previously demonstrated that TNF-alpha directly inhibits CSF-induced proliferation of primitive murine lineage-negative bone marrow progenitors (Lin-) and stem cell antigen-1 hematopoietic progenitors through the 75-kDa TNF receptor (TNF-R2), whereas TNF-alpha-induced inhibition of more committed Lin- progenitors is mediated through the 55-kDa TNF-R (TNF-R1), indicating a differential role of the two TNF-Rs in hematopoiesis. Numerous studies have demonstrated the ability of stem cell factor (SCF), a key regulator of hematopoiesis signaling through c-kit, to synergize with other hematopoietic growth factors, but little is known about cytokines capable of inhibiting hematopoiesis induced by SCF. While TNF-alpha has been demonstrated to enhance SCF-induced proliferation of myeloid leukemia blasts, the present report demonstrates that TNF-alpha, by signaling through TNF-R2, inhibits SCF-induced proliferation of normal murine Lin- and stem cell antigen-1 hematopoietic progenitors. SCF-stimulated proliferation of the hematopoietic cell line FDC-P1 was also potently inhibited by TNF-alpha and was accompanied by down-regulation of c-kit cell surface expression as well as c-kit mRNA levels. Finally, treatment of the FDC-P1 cell line with TNF-alpha resulted in increased levels of the tumor suppressor p53 mRNA, suggesting another mechanism by which hematopoietic effects of TNF-alpha may be mediated.

Type

Journal article

Journal

J Immunol

Publication Date

15/04/1995

Volume

154

Pages

3732 - 3741

Keywords

Animals, Bone Marrow Cells, Cell Division, Gene Expression Regulation, Hematopoiesis, Hematopoietic Cell Growth Factors, In Vitro Techniques, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-kit, RNA, Messenger, Receptor Protein-Tyrosine Kinases, Receptors, Colony-Stimulating Factor, Receptors, Tumor Necrosis Factor, Signal Transduction, Stem Cell Factor, Tumor Necrosis Factor-alpha, Tumor Suppressor Protein p53